KR20150041608A - Inhalable pharmaceutical compositions - Google Patents

Abstract

There is provided a method of making a composite particle for inhalation comprising a pharmaceutically active agent, said method comprising the steps of: a) providing a composite particle comprising a finely millable matrix and a solid pharmaceutical active substance, The active material has a median particle size of 50 nm to 3 占 퐉 on a volume average basis; And b) milling the composite particles in a mill without a milling body for a period of time sufficient to produce inhalable composite particles having a median aerodynamic diameter of between 1 μm and 20 μm.

Description

[0001] INHALABLE PHARMACEUTICAL COMPOSITIONS [0002]

The present invention relates to a method for preparing particles for inhalation comprising a pharmaceutically active agent.

The rationale for drug delivery through inhalation varies by type. For example, due to the nature of certain respiratory disease conditions such as infection, inflammation or bronchoconstriction, inhalation has been found to be the optimal route of administration for achieving a sufficiently high level of drug in the diseased tissue (s). In some cases, certain substances delivered via inhalation do not apply to efficacy, as is the case with some types of respiratory therapy, and may cause less inhalation systemic side effects. On the other hand, drugs intended for systemic activity can be delivered via inhalation to take advantage of the high surface area of the lungs, providing rapid drug absorption into the systemic circulation without first-pass metabolism effects associated with oral administration. In some situations, delivery of the substance to the lung may be for convenience of the patient or healthcare provider. The development of vaccine delivery to the lungs is a current concern, and if successful this will eliminate the need for injections, which are part of routine immunizations. Conventional medications delivered to the lungs are drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD), where the drug works locally in the lung tissue to prevent or alleviate symptoms such as bronchospasm. Another example would be the delivery of antibiotics to treat the presence of bacterial infections in the lungs.

Currently, there are generally three different methods used for drug delivery to the lungs. The initial drug substance was dissolved or dispersed in a liquid / gas jet, such as chlorofluorocarbon (CFC) or hydrofluorocarbon (HFA134a). In such a system, the drug substance and injectant are supplied in a canister containing a metering valve, which can be used with a device referred to as a pressurized metered dose inhaler (pMDI). At the time of administration, the patient needs to align the respiratory suction with the operation of the device. During operation of the device, the drug substance is aerosolized by the propellant. Pressurized metered dose inhalers have some disadvantages, including (in some cases) the use of ozone destructive agents (CFCs). Also, during operation, the drug substance particles leave the device at high speed due to the pressure generated by the injecting agent. This allows most of the dose to be swallowed instead of being delivered to the lungs by impacting the patient's pharynx. Many patients also have difficulty breathing to operate the device. For all the reasons mentioned above, pressurized metered dose inhalers are less optimal for delivery of drug substance to the lungs.

A second method of pulmonary drug delivery involves dissolving or dispersing the drug substance in water and then spraying the solution and suspension with a compressed air (jet) or ultrasonic atomizer. This approach is often desirable for pediatric patients who can not adjust their breathing to the operation of a pressurized metered dose inhaler. Drug delivery by spraying suffers from the drawback of being very slow. Typical commercialized nebulizers have delivery rates in the range of about 0.25 to 0.50 mL / min, resulting in drug administration times of 6 to 7 minutes or more. Spray therapy is inconvenient and requires a high level of patient compliance. For example, all sprayers must be cleaned and disinfected after each use. The jet spraying apparatus requires the use of an electrically operated air compressor, and the ultrasonic atomizing apparatus must be connected to the line voltage for operation or requires a battery. Some spray devices, including mesh screens, are only suitable for delivery of drug solutions and can not be used with suspensions. For all these reasons, the use of a sprayer is generally limited to patients who are unable to respond to device operation and inpatients with the respiratory tube in place.

The third method of pulmonary drug delivery is by inhalation of dry powder formulations. The drug substance is delivered from the delivery device located in the mouth to the lungs by the patient's breathing to the lungs. Typical dry powder formulations consist of carrier particles of an inactive component such as lactose combined with a micronized pharmaceutical active, although some devices are designed for delivery of pure micronized drug substance. The most important characteristic for the successful delivery of dry powder inhalation therapy is the aerodynamic size of aerosolized drug particles. Aerodynamic size is a measure of how drug particles behave in the air flow and depends on various factors including geometric particle size, shape, and density. The aerodynamic size also depends on how easily the particles in the powder can be separated or deaggregated from one another upon aerosolization. Thus, a strongly agglomerated tiny mouth can behave like a much larger particle when aerosolized. The aerodynamic size determines how far the particles can penetrate into the lungs. Generally, the smaller the particle size, the deeper the particles penetrate into the lungs. Inhaled particles with a diameter of less than about 1 μm are often not released into the lungs and are released out of the lungs. For drugs for systemic absorption, particles having a MMAD of 0.5 to 5 (or 1 to 3) 占 퐉 are generally preferred, requiring deep penetration into the alveolar region of the lung. In order to treat diseases of COPD, asthma and other airways, local delivery of the roads is the goal. Particles having a size of between 3 and 5 mu m are preferred for this purpose because they generally tend to settle in the conductive airways of the lungs. Since most raw drug substances are significantly larger than 1 to 5 占 퐉 in diameter, current methods of manufacturing inhalants require air jet micronization of the drug substance. Although micronization is an effective method of drug particle size reduction, it imparts a high level of electrostatic charge to the particles which adhere the particles to each other, to carrier particles in the formulation, and to the surface of the dry powder inhaler device. As a result, the delivery efficiency of conventional dry powder formulations may be relatively low, and in some cases only a third of the aerosolized material may reach the patient's airways.

There are several other key parameters in the successful delivery of therapeutic or pharmaceutical substances by inhalation of dry powder. One important parameter is the aerodynamic diameter of the particles, which is a measure of how particles behave during dispersion in air flow. In the case where the formulation contains an excipient in addition to the active agent particles, the proper content uniformity of the powder is another important property for accurate dose delivery. Another important parameter for inhaled dry powder formulations is the flowability of the powder. The powder in the device used by the patient needs to be well flowed so that a complete and consistent volume of the powder formulation leaves the device. Another important parameter for inhaled dry powder formulations is the capacity transfer efficiency, a measure of which is the fine particle fraction (FPF). Thus, the FPF provides an in vitro measurement of the efficiency of the device / agent in the delivery of active water to the lungs.

Despite advances in methods of making dry powder formulations, there is a need for particles with appropriate properties such as size, uniformity, flowability, and FPF for improved delivery of therapeutic agents to the lungs. Moreover, there is a need for a cost-effective method that can be readily used without limitations imposed by the solubility of the therapeutic agent. These and other needs are met by the present invention.

summary

Disclosed herein is a method for preparing particles for inhalation comprising a pharmaceutically active agent, the method comprising the steps of: a) providing a composite particle comprising a millable comminution matrix and a solid pharmaceutical active agent, Wherein the pharmaceutically active agent has a median particle size of 50 nm to 3 占 퐉 on a volume average basis; And b) milling the composite particles in a mill without a milling body for a period of time sufficient to produce inhalable composite particles having a median aerodynamic diameter of between 1 μm and 20 μm.

In various embodiments: the inhaled complex particles comprise a solid pharmaceutical active having median particles of 50 nm to 3 占 퐉 on a volume average basis; Inhalable composite particles have a median particle size of less than 10,000 nm in volume average size; The composite particles for inhalation are determined on a particle volume basis and have a D90 of less than 15,000 nm; The composite particles for inhalation are determined on the basis of particle volume and have a D90 of at least 2000 nm; Inhalable composite particles have a volume weighted average value (D4,3) of less than or equal to 10,000 nm; The inhalable composite particles have a volume weighted average value (D4,3) of more than 1000 nm; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of from 1 μm to 10 μm of the inhalation complex particles upon delivery from the dry powder inhaler; The inhalation complex particles can provide an aerosol having a fine particle fraction (FPF) of at least about 10% of the release dose of the pharmaceutically active agent upon delivery from the dry powder inhaler; The inhalation complex particles can provide an aerosol having a relative standard deviation (RSD) of the FPF of about 10% or less of the release dose of the pharmaceutically active agent; The inhaled complex particles may provide an aerosol having a fine particle fraction (FPF) of at least about 30% of the total recovered dose of the pharmaceutical active agent upon delivery from the dry powder inhaler; The inhalation complex particles provide an aerosol having a mass median aerodynamic diameter (MMAD) of at least about 10 [mu] m to about 10 [mu] m inhalation complex particles at delivery from a dry powder inhaler and a FPF of at least about 10% .

In various embodiments: the inhalation complex particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of inhaled complex particles of 1 [mu] m to 7 [mu] m upon delivery from a dry powder inhaler; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of 1.5 [mu] m to 5 [mu] m inhalation complex particles upon delivery from a dry powder inhaler; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of 2 μm to 5 μm inhalable composite particles upon delivery from a dry powder inhaler; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of 2 μm to 4 μm inhalable complex particles upon delivery from a dry powder inhaler; The inhalable complex particles may provide an aerosol having an emitted dose (ED) of at least about 70% upon delivery from a dry powder inhaler; The composite particles can provide an aerosol having a relative standard deviation (RSD) of less than or equal to about 10% for at least three samples delivered from a dry powder inhaler; The pharmaceutically active agent in the provided composite particle has a median size of from about 50 nm to about 1000 nm.

In various embodiments, the provided composite particles further comprise a milling aid; The millable milling matrix is crystalline; The pharmaceutically active agent is crystalline; The uniformity of the content of the solid pharmaceutical active agent dispersed in the composite particles results in a percentage difference of less than about 5.0% from the average content; The content uniformity of the pharmaceutically active agent throughout the formulation has a percent relative standard deviation (RSD) of about 5.0% or less; The inhalation complex particles have a roughness by surface ratio of at least about 1.1 (the specific surface area is measured using nitrogen absorption and the surface area is the spherical equivalent size determined by dry powder laser diffraction, Lt; / RTI >

In various embodiments: the composite particles have Rrms above a height selected from about 15 nm and Rrms is measured using atomic force microscopy; The composite particle has Rrms above a height selected from about 15 nm and Rrms is measured using a white light interference measurement; The composite particles have a median adhesion (F [50]) of less than about 150 nN as measured by atomic force microscopy; The weight of the composite particles deviates from the average weight distributed at the time of dispensing from the automated or semi-automated piling machine by a percentage of less than about 10%; The RSD from the average weight is less than or equal to about 10% when the number of samples measured is greater than 100 samples delivered from an automated or semi-automated filing machine; The step of providing the composite particles comprises the step of mixing the composition comprising a solid pharmaceutical active and a finely millable matrix in a mill comprising a plurality of milling bodies for a time sufficient to produce composite particles comprising a milling matrix and a solid pharmaceutical active agent Dry milling the substrate; Dry milling includes milling in a mill with a plurality of milling bodies; A mill without a milling body can be manufactured using a cutter mill, an end-runner mill, a roller mill, a hammer mill, a fluid energy mill, a pin mill a pin mill, an impact mill, a mechanofusion mill, a beater mill, a jet mill, and an air jet mill.

In various embodiments, the Millerbly pulverulent matrix may comprise an organic acid, an organic base, a polyol, a peptide, a protein, a fat, a fatty acid, an amino acid (aspartic acid, glutamic acid, leucine, L- leucine, isoleucine, lysine, valine, methionine, phenylalanine, Arginine, aspartic acid, glutamic acid, cysteine, alanine, serine, phenylalanine, lysine, N-acetyl-L-cysteine, or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof), carbohydrate , Mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, lactose, sucrose, raffinose, ribitol, maltose, sorbose, , 1-O-alpha-D-glucopyranosyl-D-mannitol (isomalt)), or a pharmaceutically acceptable salt thereof, It comprises at least one material selected from the solvate, hydrate, or polymorph thereof, phospholipids, triglycerides, detergent, polymer, or pharmaceutically acceptable salts thereof, pharmaceutical possible, solvate, hydrate, or polymorph.

In various embodiments: the Millerbly pulverulent matrix comprises lactose monohydrate and a pharmaceutically acceptable excipient selected from the group consisting of sodium chloride, anhydrous lactose, mannitol, glucose, sucrose, trehalose, sorbitol, 1-O- alpha -D- glucopyranosyl- ), Xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, Late, sodium ascorbate. But are not limited to, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sodium lauryl sulfate, ; PEG 6000, PEG 3000 Tween 80, Poloxamer 188, leucine, L-leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, ≪ / RTI >

In various embodiments: the composite particle further comprises a second pharmaceutically active agent, the method producing composite particles of a matrix having a solid pharmaceutical active agent dispersed in a matrix and a second pharmaceutical active agent; The composite particles are delivered from a dry powder inhaler and have a fine particle fraction ratio of the first pharmaceutical active agent and the second pharmaceutical active agent of less than about 1.2, as analyzed by NGI with an induction port and a pre-separator; Wherein the distribution of each of the first and second pharmaceutical active agents is assessed and the concentration of each of the complexes, It is used to calculate MMAD for particles.

Compositions for inhalation of pharmaceutically active composite particles prepared by any of the methods described above are also described.

A pharmaceutical active composition for inhalation comprising a plurality of composite particles comprising a millable milling matrix and a solid pharmaceutical active is also described wherein the composite particles of the milling matrix and the solid pharmaceutical active agent have a particle size of from about 1 [mu] m to about 20 [mu] m Mass median aerodynamic diameter; Wherein the pharmaceutically active agent in the composite particle has an average particle size of from about 50 nm to about 3 占 퐉.

In various aspects of such inhalation compositions: a solid pharmaceutical active having median particles of 50 nm to 3 占 퐉 on average on an inhalation complex particle volume basis; Inhalable composite particles have a median particle size of less than 10,000 nm in volume average size; The composite particles for inhalation are determined on a particle volume basis and have a D90 of less than 15,000 nm; The composite particles for inhalation are determined on the basis of particle volume and have a D90 of at least 2000 nm; Inhalable composite particles have a volume weighted average value (D4,3) of less than or equal to 10,000 nm; The inhalable composite particles have a volume weighted average value (D4,3) of more than 1000 nm; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of from 1 μm to 10 μm of the inhalation complex particles upon delivery from the dry powder inhaler; The inhalation complex particles can provide an aerosol having a fine particle fraction (FPF) of at least about 10% of the release dose of the pharmaceutically active agent upon delivery from the dry powder inhaler; The inhalation complex particles can provide an aerosol having a relative standard deviation (RSD) of the FPF of about 10% or less of the release dose of the pharmaceutically active agent; The inhaled complex particles may provide an aerosol having a fine particle fraction (FPF) of at least about 30% of the total recovered dose of the pharmaceutical active agent upon delivery from the dry powder inhaler; The inhalation complex particles provide an aerosol having a mass median aerodynamic diameter (MMAD) of at least about 10 [mu] m to about 10 [mu] m inhalation complex particles at delivery from a dry powder inhaler and a FPF of at least about 10% Can be; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of inhaled complex particles of from 1 μm to 7 μm upon delivery from a dry powder inhaler; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of 1.5 [mu] m to 5 [mu] m inhalation complex particles upon delivery from a dry powder inhaler; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of 2 μm to 5 μm inhalable composite particles upon delivery from a dry powder inhaler; The inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of 2 μm to 4 μm inhalable complex particles upon delivery from a dry powder inhaler; The inhalable complex particles may provide an aerosol having a fine particle fraction (FPF) of at least about 70% release capacity upon delivery from a dry powder inhaler; The composite particles can provide an aerosol having a relative standard deviation (RSD) of less than or equal to about 10% for at least three samples delivered from a dry powder inhaler; The pharmaceutically active agent in the provided composite particle has a median size of from about 50 nm to about 1000 nm; The provided composite particle further comprises a milling aid; The millable milling matrix is crystalline; The pharmaceutically active agent is crystalline; The uniformity of the content of the solid pharmaceutical active agent dispersed in the composite particles results in a percentage difference of less than about 5.0% from the average content; The content uniformity of the pharmaceutically active agent throughout the formulation has a percent relative standard deviation (RSD) of about 5.0% or less; The inhalation composite particles have a roughness ratio by surface area of greater than about 1.1 (the specific surface area is measured using nitrogen absorption and the surface area is calculated from the spherical equivalent size determined by dry powder laser diffraction); The composite particles have Rrms above a height selected from about 15 nm and Rrms is measured using atomic force microscopy; The composite particle has Rrms above a height selected from about 15 nm and Rrms is measured using a white light interference measurement; The composite particles have a median adhesion (F [50]) of less than about 150 nN as measured by atomic force microscopy; The weight of the composite particles deviates from the average weight distributed at the time of dispensing from the automated or semi-automated piling machine by a percentage of less than about 10%; The RSD from the average weight is less than or equal to about 10% when the number of samples measured is greater than 100 samples delivered from an automated or semi-automated filing machine; The composite particles further comprise a second pharmaceutically active agent, the method producing composite particles of a matrix having a solid pharmaceutical active agent dispersed in a matrix and a second pharmaceutically active agent; The composite particles are delivered from a dry powder inhaler and have a fine particle fraction ratio of the first pharmaceutical active agent and the second pharmaceutical active agent of less than about 1.2, as analyzed by NGI with an induction port and a pre-separator; Wherein the distribution of each of the first and second pharmaceutical active agents is assessed and the concentration of each of the complexes, It is used to calculate MMAD for particles.

Any of the aforementioned pharmaceutical compositions formulated in unit dosage form will also be described. In various embodiments: the pharmaceutical composition comprises a gelatin capsule, and the composition is suitable for use in a dry powder inhaler.

A dry powder inhaler comprising the pharmaceutical composition described above is also described.

Figure 1 shows representative SEM data of arrangement 4J (10,000x magnification).
Figure 2 shows representative SEM data of arrangement 4J (100,000x magnification).

All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials relating to the publications cited. The publications discussed herein are provided only for disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is prior to such publication by a prior invention. Moreover, the disclosure date provided herein may be different from the actual disclosure date, which may require independent verification.

Specific abbreviations used herein are as follows: "AFM" is an abbreviation for atomic force microscopy; "CI" is an abbreviation for Anderson Cascade Impactor; "MSLI" stands for Multi- Stage Liquid Impinger; "NGI" stands for Next Generation Impactor.

In the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "functional group", "alkyl", or "residue" includes mixtures of two or more such functional groups, alkyl, or functional groups and the like.

Ranges may be expressed herein as "about" one particular value, and / or to "about" another specific value. When such a range is expressed, another aspect includes one particular value and / or another specific value. Similarly, when values are expressed as approximations by the use of the preceding "about ", it will be understood that the particular value forms another aspect. It will also be appreciated that each endpoint of the range is significant compared to the other endpoint, and both are independent of the other endpoint. It is also understood that there are several values disclosed herein, and that each value is also disclosed herein as a "about" specific value in addition to the value itself. For example, when the value "10" is to be started, "about 10" It is also understood that each unit between two specific units is also disclosed. For example, when 10 and 15 are initiated, 11, 12, 13, and 14 are also disclosed.

Reference to weight parts of certain elements or components in the composition and in the appended claims reflects the weight relationship between the elements or components and any other elements or components in the composition or article in which the weight parts are expressed. Thus, in the compounds containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2: 5 and are present in such proportions irrespective of whether additional components are contained in the compound. The percent by weight (wt.%) Of the ingredient, by the contrary, unless otherwise specifically stated, is based on the total weight of the formulation or composition in which the ingredient is included.

As used herein, the terms " administering "and" administraiton "refer to providing a pharmaceutical formulation to a subject by inhalation or nasal administration. Administration may be continuous or intermittent. In various embodiments, the agent can be administered therapeutically; In other words, it can be administered for the treatment of an existing disease or condition. In yet another various embodiments, the agent can be administered prophylactically; In other words, it can be administered for the prevention of diseases or conditions.

As used herein, the term "blend" refers to a blend of active pharmaceutical ingredients and pharmaceutical excipients, combined with each other in a process having the effect of dispensing the active water and excipient particles in a uniform distribution throughout the final powder combination, Refers to the resulting mixture of excipient particles. In this definition, the term excipient and matrix are interchangeable. A collection of composite particles prepared by the disclosed method is an example of a blend. Typically, the formulations are prepared using a simple blending process that does not involve granulation but can include a milling step.

As used herein, the term "carrier excipient " refers to a pharmaceutical excipient suitable for use in an oral-inhaled formulation, which may be combined with inhaled complex particles for the manufacture of a formulation for therapeutic use.

As used herein, the term "carrier matrix" refers to any material that has been milled with a pharmaceutically active agent and incorporated into a composite particle having nanoparticles of a pharmaceutically active agent.

As used herein, the term "chemically inert" refers to a substance that does not react chemically with a pharmaceutically active agent or millable milling matrix, for example a milling body.

As used herein, the term " co-crystal "refers to the physical association of two or more molecules that are stable through non-porous interactions. One or more components of such molecular complexes provide a stable framework for the crystal lattice. In certain instances, guest molecules are incorporated into the crystal lattice as hydrates or solvates. For example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et al., The Royal Society of Chemistry , (2004), 1889-1896. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

As used herein, the term "composite particles" refers to particles comprising particles of a millable milling matrix (milled or partially milled) combined with larger particles and particles of a pharmaceutically active agent. In some cases, the particles of the pharmaceutically active agent and the particles of the millable pulverulent matrix are dispersed in the composite particles. The composite particles may comprise more than one pharmaceutically active agent or particles of more than one millable filler matrix. The composite particles may further comprise additional materials such as milling aids. The particles of the pharmaceutically active agent can be nanoparticles and / or microparticles, but are typically nanoparticles. The particles of the millable milling matrix may also be nanoparticles and / or microparticles.

As used herein, the term "content uniformity" refers to uniformity in which the pharmaceutically active agent is distributed throughout the formulation. Formulations with good content uniformity will have the same concentration of the pharmaceutical active in different samples taken from different positions (e.g., stomach, middle and lower) in the formulation. Typically, the content uniformity is determined by evaluating the sample by HPLC or similar techniques to determine the concentration of the active in the sample. Typically, the content uniformity is expressed as a percentage (%) deviation of several samples from the known concentration of the total formulation. In the bulk powder sample, the content uniformity can be measured from three or more samples. When the powder is filled into a packaging container such as a hard capsule or a foil blister pack, some packaging will be evaluated to determine the content uniformity (typically 10 randomly selected from a larger number). When a package such as a capsule is evaluated for determining the content uniformity of the powder, the evaluation should be corrected for the total weight of the powder in each package. One common measure for content uniformity is the average concentration of the total formulation or the percent deviation of each sample from known concentrations. In that case the detailed requirement would be that the sample does not have a deviation of more than a certain percentage. The second common measure is the relative standard deviation (RSD) of the sample evaluation from the mean (and also the mean of the sample of the bulk powder at the known concentration).

As used herein, unless otherwise specified in context, the term " dry mill "or variations such as" dry milling "refer to milling at least in a substantial part of the liquid. When a liquid is present, it is present in an amount such that the contents of the mill retain the characteristics of the dry powder. In some cases dry milling occurs in the complete absence of liquid.

As used herein, the term "dry powder laser diffraction" refers to a laser diffraction measurement in which compressed air is used to disperse dry powder into an air stream passing through a measurement area.

As used herein, the term "particle size" may refer to a measurement of the distribution of individual particles or particles. The terms "particle size distribution,""average particle size,""median particle size," and "mean particle size" are not all individually the same size, , Nanometer or micrometer). ≪ / RTI > These parameters can be measured by various techniques including dynamic light scattering, static light scattering, laser diffraction, precipitation, time of flight, or other methods known to those skilled in the art. The particle size distribution can also be quantified by a size corresponding to a specific percentile (D _x ) of the distribution, wherein the specific percentage (x) of the population (by volume basis, but not by weight) is less than the defined size. For example, a distribution having a D ₉₀ value of 500 nm (by volume) means that 90% of the distribution has a size less than 500 nm. As used herein, the terms "D ₅₀ " and "median particle size" are used interchangeably. The terms " average particle size "and" mean particle size "are used interchangeably and can be calculated from the size distribution by methods known to those skilled in the art. The mean value particle size may also be indicated by the term "D _(4,3) " which refers to the method of calculating the mean value of the particle distribution.

As used herein, the term "effective aerodynamic size" refers to the characterization of the particle distribution in the measurement in an air stream. The effective aerodynamic particle size may be expressed as a median, mean, mean, or representation of a size corresponding to a specified percentile determined by aerodynamic measurement techniques known to those skilled in the art.

As used herein, the terms "release dose" and "ED" are interchangeable and refer to the fraction of total available capacity in the device delivered by the inhaler device. This is often expressed as a percentage.

As used herein, the terms "fine particle fraction" and "FPF" are interchangeable and refer to fractions of pharmaceutical active agents having an aerodynamic diameter of less than about 4-6 μm. Unless otherwise stated, as used herein, the FPF is determined using an NGI with an induction port and a pre-separator. Other methods known to those skilled in the art for PFP determination include using a Multi Stage Liquid Impinger (MSLI) with an induction port or Anderson Cascade Impactor (CI) with an induction port and a pre-separator. The FPF is expressed as a percentage of the total capacity and is typically expressed as a percentage of the total capacity of less than about 4-6 microns. Unless otherwise stated, FPF is the fraction relative to the release capacity. Another definition is the FPF relative to the total recovery capacity (TRD), and if this is intended, it is expressed as FPF (TRD). The total recovered capacity is the sum of the discharge capacity and the capacity remaining in the device / capacity packaging container. It should be noted that the disclosed composite particles comprise a pharmaceutically active agent that uniformly flocculates into the composite particles, and thus the FPF is also an index of the fraction of the composite having an aerodynamic diameter of less than about 4-6 microns.

As used herein, the term "flowable " refers to a powder having physical properties that make it suitable for further processing using the pharmaceutical composition and typical equipment used in the manufacture of the formulation.

As used herein, the term "FPF uniformity ratio" refers to the ratio of two FPF values determined from an evaluation of the two individual pharmaceutical actives present in a single composite particle composition. The ratio is calculated by dividing the larger FPF by the smaller. It should be noted that this only means that there is more than one active contained in the composite composition. When the uniformity ratio is approximately 1, this is an indication that the two pharmaceutically active agents have a very uniform distribution throughout the composite composition.

As used herein, the term "geometric standard deviation" or "GSD" is used interchangeably and refers to an aerodynamic particle size distribution and is calculated as follows: GSD = (d ₈₄ / d ₁₆ ) ^1/2 . Unless otherwise stated, as used herein, GSD is determined using an NGI with an induction port and a pre-separator. Other methods for determining the GSD known to those skilled in the art include using an MSLI with an induction port or a CI with an induction port and a pre-separator. As described above for the definition of FPF, the disclosed composite particles comprise a pharmaceutically active agent composite that is uniformly agglomerated within the particles, so even though the GSD is determined from the evaluation of the active material, this is a measure of the aerodynamic size distribution of the composite particles to be.

As used herein, the phrase "identified as requiring treatment of a disorder" or the like, refers to the selection of a subject based on the need for treatment of the disorder. For example, a subject may be identified by a skilled practitioner in the art as having a need for treatment of a disorder (e.g., respiratory disorder) based on a diagnosis first, followed by treatment for the disorder. Identification is, in one aspect, considered to be performed by someone other than the person making the diagnosis. Further, in another embodiment, administration is contemplated to be performed by a person who will perform the administration at a later time.

As used herein, the phrase "complex for inhalation" refers to a powder comprising complex particles having the correct aerodynamic diameter to be orally inhaled into the lungs of an object. The object can be human.

As used herein, the term "inhibit " refers to the process of controlling, preventing, limiting, and slowing, stopping, or reversing progression or severity, and to such effect on the resulting clinical or medical symptoms .

As used herein, the term "median adhesive force" or "F [50]" refers to the median adhesion between inoculum composite particles measured by atomic force microscopy (AFM) ) ≪ / RTI > Specifically, F [50], as used herein, refers to Adi et al. And is measured by nuclear microscopy using the method described in European Journal of Pharmaceutical Sciences , 35 (2008) 12-18.

As used herein, the terms "mass median aerodynamic diameter" and "MMAD" are interchangeable and refer to aerodynamic diameters in which 50% of the particles by mass and 50% by mass are smaller. MMAD can be measured using Next Generation Impactor (NGI) with induction port and pre-separator. Other methods known to those skilled in the art for MMAD determination include using a Multi Stage Liquid Impinger (MSLI) with an induction port or a Cascade Impactor (CI) with an induction port and a pre-separator. The MMAD may also be determined using flight time measurements known to those skilled in the art. As pointed out above with respect to the definition of FPF, although the disclosed complex particles comprise a pharmaceutical active agent that uniformly flocculates in the composite particles, and thus even though the MMAD is determined from the evaluation of the active material, this is a measure of the aerodynamic size of the composite particles to be. The MMAD is equivalent to the aerodynamic D50 value on a volumetric basis after correction for particle density.

As used herein, the term "MMAD homogeneity ratio" refers to the ratio of two MMAD values determined from an evaluation of the two individual pharmaceutical actives present in a single composite particle composition. The ratio is calculated by dividing the larger MMAD by the smaller. It should be noted that this only means that there is more than one active contained in the composite composition. When the MMAD uniformity ratio is approximately 1, this is an indication that the two pharmaceutically active agents have a very uniform distribution throughout the composite composition.

As used herein, the term "millable" refers to a millable milling matrix that reduces particle size under dry milling conditions of the method of the present invention.

As used herein, the term "Millable Grain Matrix" refers to any inert agent that can be combined, combined, and milled to provide the composite particles with the pharmaceutically active agent. The terms " co-grinding matrix "and" matrix "are interchangeable with" grinding matrix ".

As used herein, the term "nanoparticle" refers to particles having a size of about 1000 nm or less.

As used herein, the term " passive laser diffraction " refers to a process of size measurement of a dry powder by using laser diffraction wherein the dry powder is dispersed in the air stream exiting the inhaler and throughout the measurement area. The airflow through the device is within the normal range for human suction. The airflow will typically range from 20-100 liters / minute, but is not limited thereto. Thus, the dry powder is mechanically dispersed by the air exiting the inhalation device, not by the particle size device.

As used herein, the term "pharmaceutically active agent " refers to any substance that, upon administration to a subject, has therapeutic, diagnostic, and biological and / or pharmacological effects desired. As used herein, the terms may be used interchangeably with "active material "," active compound ", and "biologically active material ". The pharmacologically active agent may be used for the treatment, recovery, prevention, or diagnosis of a disease, or may be used to improve physical or mental well-being. As used herein, the term "roughness by surface area" refers to the ratio of the specific surface area (SSA) of the composite measured by the BET isotherm and the surface area mapped from the laser diffraction particle size measurement of the composite, This is by powder laser diffraction. Surface roughness is a measure of the roughness of the particles. That is, when the ratio of the actual SSA to the calculated surface area is large, the surface is rougher.

As used herein, both the terms "roughness-root mean squared" and "Rrms" refer to the square root of the root mean square, where the root mean square is divided by the number of data points ) ≪ / RTI > Specifically, Rrms, as used herein, refers to Adi et al. Is measured by atomic force microscopy or scanning white light interference measurement according to the method described in [ Langmuir , 24 (2008) 11307-11312].

As used herein, the term "separation" refers to stratification of the particle size distribution of the powder or blend. This may be caused by any physical process, but typically occurs when the powder or formulation undergoes flow or other movement. Examples of processes that can cause separation include, but are not limited to, transport, blending and flow in a hopper or other processing facility. The powder or combination in an undisplaced state will have a uniform particle size distribution across the entire powder or blend and thus any sample taken from any part of the bag or container holding the powder (e.g., top, middle, bottom) Will provide the same particle size distribution. In a powder that has undergone separation, a portion of the powder will have larger particles than the other portion and some will have smaller particles than the other portions of the powder. In powders with segregation, samples taken from various positions (e.g., stomach, middle, bottom) in the bag or container holding the powder will typically exhibit slight differences in particle size distribution. In some cases, for the powder separation test, a forced separation method may be used to evaluate any changes in the content uniformity after separation. An example of forced separation is to place the powder in a tube and rotate the tube for a long time with a slight tilt to separate the large and small particles.

The compounds described herein contain atoms in both natural isotope abundance ratio and non-natural abundance ratio. However, due to the fact that one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic mass or mass number typically found in nature, the disclosed compounds may be the same isotopically labeled or isotopically substituted compounds as described. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as isotopes of ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O, ³⁵ S, ¹⁸ F, and ³⁶ Cl. The compounds further include their prodrugs and are within the scope of the present invention, or a pharmaceutically acceptable salt of such a prodrug or said compound containing the aforementioned isotopes and / or other isotopes of other atoms. Incorporation of certain isotopically labeled compounds of the present invention, for example radioactive isotopes such as ³ H and ¹⁴ C, is useful in drug and / or substrate tissue distribution assays. Tritium, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for ease of manufacture and detection sensitivity. Also, substitution with heavier isotopes such as deuterium, i.e., ² H, may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements , And thus may be desirable in some situations. The isotope labeled compounds of the present invention and their prodrugs can generally be prepared by substituting the isotope ratio reagent with an easily available isotope labeled reagent and performing the following procedure.

The compounds described in the present invention may exist as solvates. In some cases, the solvent used to prepare the solvate is an aqueous solution, and if so, the solvate is often referred to as the hydrate. The compound may exist as a hydrate, which may be obtained, for example, by recrystallization from a solvent or aqueous solution. In this regard, one, two, three or any number of solvent or water molecules may be combined with the compounds according to the invention to form solvates and hydrates. Unless otherwise stated, the present invention includes all such possible solvates.

It is well known that chemicals form solids that exist in many different ordered states, referred to as polymorphic forms or variants. Several different variations of the polymorphic material may differ significantly in their physical properties. The compounds according to the invention may exist in a variety of different polymorphic forms, whereby it is possible that certain modifications are metastable. Unless stated to the contrary, the present invention includes all such polymorphic forms.

Other definitions of selected terms used herein may be found within the detailed description of the invention and apply in its entirety. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

A. Preparation of composite particles

1. Composite particles

In one aspect, the invention relates to a composite particle comprising a millable milling matrix and a pharmaceutically active agent. In another embodiment, the composite particles may further comprise milling aids.

While not wishing to be bound by any particular theory, the disclosed method provides, at least in some cases, composite particles wherein the active particles are uniformly distributed or substantially uniformly distributed throughout the complex particles, such that each composite particle has the same proportion of A pharmaceutically active agent and a millable milling matrix. Thus, if separation occurs, the formulation will maintain good content uniformity. In contrast, conventional formulations made with active particles smaller than the excipient particles will have poor content uniformity if the formulations are separated.

Again, not wishing to be bound by any particular theory, it is believed that the pharmaceutical active is incorporated, at least in some cases, into the composite particle such that the majority of the exposed surface of the composite particle is a matrix material. Accordingly, the composite generally has the properties of a matrix material. Since many active substances are substantially cohesive, this degrades inter-particle interactions. When the weight percent of the pharmaceutically active agent is very low, the composite particles are almost completely composed of the matrix material. In this case, the effect of the active material on particle particle interaction is almost completely eliminated. Thus, the agent has only one type, or mainly one type of particle interaction. In conventional formulations, there are several particle-particle interactions that complicate the development of appropriate formulations and the ability to use pharmaceutically active agents as desired.

Another advantage of the nature of the composite particles provided by the disclosed method is that a matrix such as lactose may be used with the lactose as a carrier excipient in a dry milling step if a carrier excipient is needed to prepare a formulation suitable for therapeutic use. Thus, particle particle interactions are simplified because they are with similar materials.

While not wishing to be bound by any particular theory, it is believed that another beneficial property of the disclosed composite particles is, at least in some cases, perhaps an improved powder flow resulting from relative surface roughness that reduces surface contact and reduces cohesiveness.

2. Method for manufacturing a pharmaceutically active composition for inhalation

Described herein is a method for manufacturing a composite particle for inhalation comprising a pharmaceutically active agent, the method comprising the steps of:

a) providing composite particles comprising a pulverulent finely powdered matrix and a solid pharmaceutical active, wherein the pharmaceutically active agent has a median particle size of from 50 nm to 3 μm on a volume average basis; And

b) milling the composite particles in a mill without a milling body for a period of time sufficient to produce inhalable composite particles having a median aerodynamic diameter of between 1 μm and 20 μm.

In another embodiment, milling in a mill without a milling body can be carried out (step b) using a milling machine such as a cutter mill, an end-runner mill, a roller mill, a hammer mill, a fluid energy mill, a pin mill, an impact mill, a mechanofusion mill, Milling in a mill selected from a jet mill and an air jet mill. In another embodiment, milling in a mill without a milling body is milling in an air jet mill. In another embodiment, the composite particles after air jet milling have an effective aerodynamic size from about 2 [mu] m to about 7 [mu] m.

In another embodiment, the step of providing the composite particles comprises the steps of: (a) providing an effective aerodynamic size of from about 1 [mu] m to about 20 [mu] m (e.g., 2 to 18, 4 to 16, 6 to 20, 8 to 20 [ Milling the mixture of the solid pharmaceutical active agent and the millable milling matrix in a mill comprising a plurality of milling bodies for a time sufficient to produce complex particles of the milling matrix having a solid pharmaceutical active having . In yet another aspect, dry milling is milling in a mill having a plurality of milling bodies. In another embodiment, the composite particles produced by dry milling have an effective aerodynamic size from about 5 [mu] m to about 15 [mu] m. In another embodiment, the composite particles produced by dry milling have an effective aerodynamic size from about 10 [mu] m to about 20 [mu] m. In another embodiment, the dry milled mixture further comprises a milling aid. In another embodiment, the dry milled mixture further comprises one or more milling aids. In another embodiment, the dry milled mixture further comprises at least one pharmaceutically active agent.

In another embodiment, a method for preparing a pharmaceutically active composition for inhalation comprises the steps of: (a) milling a mill containing a plurality of milling bodies for a time sufficient to produce nanoparticles of an at least partially dispersed pharmaceutical active Dry milling the solid pharmaceutical active and millable milling matrix; And (b) milling the formulation produced in step (a) in a mill-free mill to form particles for inhalation comprising a pharmaceutically active agent and a millable milling matrix. In another embodiment, the particles of the pharmaceutically active agent dispersed in the composite particles are nanoparticles. In another embodiment, the mill used in the second step is an air jet mill. In another embodiment, the pharmaceutically active agent has a median particle size of about 1000 nm or less on a volume basis. In another embodiment, the pharmaceutically active agent has a median particle size (e.g., a median size of less than 400, 300, or 200 nm) of less than about 500 nm on a volume basis, or has a median particle size of less than about 500 nm, have a D _50. In another embodiment, the composite particles comprising a pharmaceutically active agent and a millable pulverulent matrix have a composite particle size of about 10 [mu] m or less. In another embodiment, the composite particles comprising a pharmaceutically active agent and a millable milling matrix have a composite particle size of about 5 [mu] m or less.

3. Dry milling

a. Milling mix

In one aspect, the invention relates to a method comprising dry milling of a mixture comprising a solid pharmaceutical active and a millable milling matrix. In another embodiment, the mixture further comprises one or more milling aids. In another embodiment, the mixture further comprises an accelerator, wherein the accelerator is added to the mixture prior to completion of the dry milling step.

In another embodiment, the millable milling matrix is a single material or a mixture of two or more materials in any proportion. In another embodiment, the concentration of the single (or first) material is in the range of 5-99.9%, 10-95%, 15-85%, 20-80%, 25-75%, 30-60%, and 40-50% , Where the percentages are given as percent by weight (w / w). In another embodiment, the concentration of the second or further substance is 5-50%, 5-40%, 5-30%, 5-20%, 10-40%, 10-30%, 10-20%, 20- 40%, and 20-30%, wherein percent is given as weight percent (w / w). In another embodiment, when the second or further material is a surfactant, polymer, lubricant or lubricant in the presence, the concentration may range from 0.1-10%, 0.1-5%, 0.1-2.5%, 0.1-2% 0.5 to 5%, 0.5 to 3%, 0.5 to 2%, 0.5 to 1.5%, 0.5 to 1%, 0.75 to 1.25%, 0.75 to 1% and 1% w / w).

In another embodiment, the milling aid is present in the range of 0.1-10%, 0.1-5%, 0.1-2.5%. Selected from 0.1-2%, 0.1-1%, 0.5-5%, 0.5-3%, 0.5-2%, 0.5-1.5%, 0.5-1%, 0.75-1.25%, 0.75-1%, and 1% Concentration, where the percent is given as weight percent (w / w).

b. Milling equipment

In one aspect, dry milling equipment is a mill comprising a plurality of milling bodies. In another embodiment, the mill comprising a plurality of milling bodies may be a ball mill, a sand mill, a bead mill, a pearl mill, a basket mill, A ball mill, a planetary mill, a vibratory action ball mill, a multiaxial shaker / mixer, a stirred ball mill, a horizontal small media mill, And is selected from multi-ring pulverizing mills. In another aspect, a mill containing a plurality of milling bodies may be an attritor mill, a nutating mill, a tower mill, a planetary mill, a vibratory mill, and a gravity- Is selected from a gravity-dependent-type ball mill. In another embodiment, the mill comprising a plurality of milling bodies is a ball mill. In another aspect, the milling media in the milling machine is mechanically agitated by one, two or three rotational shafts. In another embodiment, the dry milling operation is adjusted to produce nanoparticles of the pharmaceutically active agent in a continuous mode.

In yet another aspect, dry milling may be accomplished using an agitator mill (horizontal or vertical), a Newtating mill, a tower mill, a pearl mill, a planetary mill, a vibrating mill, an eccentric vibratory mill, A mill, a rod mill, and a crusher mill.

c. Processing time

In one embodiment, the dry milling is carried out for 10 minutes to 2 hours, 10 minutes to 90 minutes, 10 minutes to 1 hour, 10 minutes to 45 minutes, 10 minutes to 30 minutes, 5 minutes to 30 minutes, 5 minutes to 20 minutes, 2 Min to 10 min, 2 min to 5 min, 1 min to 20 min, 1 min to 10 min, and 1 min to 5 min.

In another embodiment, the dry milling of the pharmaceutically active agent and the millable milling matrix is for the shortest time necessary to form the composite particles comprising the pharmaceutically active agent and the millable milling matrix. In another embodiment, the dry milling of the pharmaceutically active agent and the millable milling matrix is for a period of time during which contamination from the media mill and / or a plurality of milling bodies is minimized. The time varies greatly depending on the pharmaceutically active agent and millable milling matrix, and can be as short as 1 minute to several hours. In another embodiment, a dry milling time of more than two hours can cause degradation of the pharmaceutical active and an increase in the level of undesirable contaminants.

In yet another embodiment, the total milling time depends on the type and size of the milling media as well as the milling media, the weight ratio of the milling mill mixture to the pharmaceutically active agent and the millable milling matrix mixture, the chemical and physical properties of the pharmaceutical active and the milling matrix, And adjusted according to other parameters that can be experimentally optimized by a skilled person in the field.

d. Milling body

In one aspect, dry mills having a plurality of milling bodies use milling media made from materials selected from ceramics, glass, polymers, ferromagnets and metals. In another embodiment, the milling media is a steel ball having a diameter selected from 1 to 20 mm, 2 to 15 mm, and 3 to 10 mm. In another embodiment, the milling media is a zirconium oxide ball having a diameter selected from 1 to 20 mm, 2 to 15 mm, and 3 to 10 mm. In another embodiment, the milling body is a steel ball having a diameter selected from about 1 to 20 mm. In another embodiment, the milling body has a density of from about 1 to about 15 g / cm < ^{3 &} gt ;. In another embodiment, the milling body preferably has a density of about 1 to about 8 g / cm < ^{3 &} gt ;.

In another embodiment, the milling body is chemically inert and rigid. In another embodiment, the milling body is inherently resistant to fracture and corrosion in the milling process. In another aspect, the milling body is provided in the form of a body that may have any of a variety of smooth, regular shapes, planes or curved surfaces and may be free of sharp or protruding edges. For example, a suitable milling body may be in the form of a body having an ellipsoidal, oval, spherical or staff column shape. In another aspect, the milling body may include one or more of a bead, a ball, a sphere, a bar, a staff pole, a drum or a radius-end staff pole (i.e., a staff pole having a hemispherical basis with the same radius as the cylinder) .

The milling body may include various materials such as ceramics, glass, metal or polymer compositions in particulate form. Suitable metal milling bodies are typically spherical and can generally include excellent hardness (i.e., RHC 60-70), roundness, high abrasion resistance, and narrow size distribution. In another embodiment, the metallic material may be selected from AISI 52100 type chromium steel, 316 or 440C type stainless steel or AISI 1065 type high carbon steel. A suitable ceramic milling body may be selected from a variety of ceramics, for example, ceramics, preferably with sufficient hardness and resistance to breakdown and also with a sufficiently high density to allow breakage or breakage during milling to be avoided. In yet another embodiment, the ceramic material is selected from the group consisting of stearate, aluminum oxide, zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, Lt; / RTI > In another embodiment, the glass milling body is spherical (e.g., beads), has a narrow size distribution, is durable, and includes, for example, lead-free soda lime glass and borosilicate glass. In yet another embodiment, the polymer milling media is substantially spherical and has sufficient hardness and friability to avoid breakage or breakage during milling, abrasion resistance that minimizes wear resulting in contamination of the product, , And various polymer resins free of impurities such as residual monomers. In another embodiment, the polymeric resin is selected from the group consisting of crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonate, polyacetal, vinyl chloride polymers and copolymers , Polyurethane, polyamide, high-density polyethylene, polypropylene and the like. The use of polymer milling media for milling materials with very small particle sizes (as opposed to mechanochemical synthesis) is disclosed, for example, in U.S. Patent Nos. 5,478,705 and 5,500,331. In another embodiment, the polymeric resin has a density in the range of about 0.8 to about 3.0 g / cm < ^{3 &} gt ;. Alternatively, the milling media can be composite particles comprising dense core particles having a polymeric resin deposited on the core particles. The core particles may be selected from materials known to be useful as milling media, such as glass, alumina, zirconia silica, zirconium oxide, stainless steel, and the like. In another embodiment, the core material has a density of greater than about 2.5 g / cm < ^{3 &} gt ;. In another aspect, the milling media is formed from a ferromagnetic material, thereby facilitating removal of contaminants resulting from abrasion of the milling media by use of a magnetic separation technique.

Each type of milling body has its own advantages. For example, metals have the largest specific gravity, which increases the grinding efficiency due to the increased impact energy. The metal cost is low to high, but metal contamination of the final product can be a problem. Glass is advantageous in terms of low cost and availability of small beads as small as 0.004 mm. However, the specific gravity of the glass is lower than other media and significantly longer milling times are required. Finally, ceramics are advantageous in terms of low wear and contamination, ease of cleaning, and high hardness.

e. Milling conditions

In one embodiment, the total combined amount of pharmaceutically active agent and millable milling matrix in the mill at any time is about 200 g, 500 g, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg , 75 kg, 100 kg, 150 kg, and 200 kg. In another embodiment, the total combined amount of pharmaceutically active agent and milling matrix in the mill at any time is less than about 2000 kg.

4. Milling in mill without milling body

In one aspect, the present invention relates to a milling step involving milling in a mill without a milling body. In another embodiment, composite particles are provided and milling is performed on the composite particles in a mill without a milling body. In another embodiment, the composite particles are prepared by dry milling in a first step and the composite particles are further milled in a mill without a milling body in a second step. In another embodiment, the mill without milling body is selected from a cutter mill, an end-runner mill, a roller mill, a hammer mill, a fluid energy mill, an impact mill, a mechanofusion mill, a bitter mill, a jet mill and an air jet mill.

In another embodiment, the sub-particles of the pharmaceutically active agent in the composite particles after milling in a mill without a milling body have an average particle size of about 50 nm to about 3 μm.

In another embodiment, after milling in a mill without a milling body, the composite particles have a median particle size of about 10,000 nm or less. In another embodiment, after milling in a mill without a milling body, the composite particles are determined on a particle volume basis and have a D90 of about 15,000 nm or less. In another embodiment, after milling in a mill without a milling body, the composite particles are determined on a particle volume basis and have a D90 of at least 2000 nm. In another embodiment, after milling in a mill without a milling body, the composite particles have a volume weighted average value D4,3 of about 10,000 nm or less. In another embodiment, after milling in a mill without a milling body, the composite particles have a bulk weighted mean (D4,3) of at least about 1000 nm.

In another embodiment, the mill without a milling body is an air jet mill. In another embodiment, the air jet mill is of a size selected from 2 inches, 4 inches, 8 inches, 10 inches, 15 inches, 20 inches, 30 inches and 42 inches. In another embodiment, the air pressure in the air jet mill is selected from 1 bar, 2 bar, 3 bar, 4 bar, 5 bar, 6 bar, 7 bar, 8 bar, 9 bar and 10 bar. In another embodiment, the powder feed rate to the air jet mill is 0.5 kg / hr, 1.0 kg / hr, 5 kg / hr, 10 kg / hr, 15 kg / hr, 20 kg / kg / hr, 75 kg / hr, 100 kg / hr, 150 kg / hr, 200 kg / hr, 500 kg / hr and 1000 kg / hr.

In another embodiment, the accelerator is added to the resulting composite particles at the end of milling in a mill without a milling body and then further processed in another milling apparatus such as a mechanofusion mill, a cyclomixer, or an impact mill. The impact mill for further processing is selected from a ball mill and a jet mill. Alternatively, in another embodiment, further processing is performed in a high pressure homogenizer. In another embodiment, the further processing is carried out using a combination of two or more of a mechanofusion mill, a cyclomixer, an impact mill, or a high pressure homogenizer.

B. Substances used in the manufacture of composite particles

1. Millable milling matrix

In one aspect, the invention relates to a millable milling matrix for use in the preparation of composite particles comprising a pharmaceutically active agent and a millable milling matrix. In another embodiment, the millable milling matrix is a particle size similar to a pharmaceutically active agent. In another embodiment, the particle size of the millable milling matrix is substantially reduced but not as small as the pharmaceutically active agent material. In another embodiment, the Millerbly pulverulent matrix is selected from the group consisting of: Substances considered to be Generally Regarded as Safe (GRAS) for inhalable pharmaceutical products or for use in veterinary preparations Substances considered acceptable. In another embodiment, the millable milling matrix may be an inorganic or organic material.

In another embodiment, the Millerbly pulverulent matrix may be a mixture of organic acids, organic bases, sugars, polyols, peptides, proteins, fats, fatty acids, amino acids, carbohydrates, phospholipids, triglycerides, detergents, Cargo, hydrate, or polymorph thereof. In another embodiment, the millable milling matrix is sodium chloride.

In another embodiment, the millable milling matrix is selected from the group consisting of mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, lactose, sucrose, raffinose, , Carbohydrates selected from maltose, sorbose, cellobiose, sorbose, trehalose, maltodextrin, dextran, inulin, 1-O-alpha-D-glucopyranosyl-D- mannitol (isomalt) , Or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof.

In another embodiment, the millable milling matrix is selected from aspartic acid, glutamic acid, leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, serine, phenylalanine, Amino acid, wherein the amino acid may be in D, L or DL configuration as appropriate for the end use. N-acetyl-L-cysteine, or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof.

In another embodiment, the millable milling matrix comprises a phospholipid selected from dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, Or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

In another embodiment, the millable milling matrix is a fatty acid selected from palmitic acid, stearic acid, erucic acid, behenic acid, lauric acid, or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof. In another embodiment, the fatty acid is selected from sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, magnesium stearate, calcium stearate, sodium stearate, lithium stearate, sodium lauryl sulfate, magnesium lauryl sulfate Or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof.

In another embodiment, the millable milling matrix is a salt of an organic acid selected from sodium gluconate, magnesium gluconate, sodium citrate, sodium ascorbate. In another embodiment, the millable milling matrix is human serum albumin. In another embodiment, the millable milling matrix is a fat selected from lecithin and soy lecithin. In another embodiment, the millable milling matrix is selected from Dynsan 118, Cutina HR, gelatin, hiropromellose, polyethylene glycol, PEG 6000, PEG 3000, PEGS, Tween 80, and Poloxamer 188.

In another embodiment, the Millerbly pulverulent matrix comprises lactose monohydrate and at least one compound selected from the group consisting of sodium chloride, anhydrous lactose, mannitol, glucose, sucrose, trehalose, sorbitol, 1-O- alpha-D- glucopyranosyl- Malt), xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium But are not limited to, citrate, sodium ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, Lauryl sulfate, magnesium lauryl sulfate, PEG 6000, PEG 3000 Tween 80, Poloxamer 188, Wherein the amino acid comprises at least one substance selected from the group consisting of an amino acid, an amino acid, a glycine, an isoleucine, a lysine, a valine, a methionine, a phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, D-configuration, L-configuration, or DL-configuration.

In another embodiment, the Millerbly pulverulent matrix comprises anhydrous lactose and an effective amount of a compound selected from the group consisting of sodium chloride, lactose monohydrate, mannitol, glucose, sucrose, trehalose, sorbitol, 1-O-alpha-D- glucopyranosyl- Malt), xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium But are not limited to, citrate, sodium ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, Lauryl sulfate, magnesium lauryl sulfate, PEG 6000, PEG 3000 Tween 80, Poloxamer 188, Wherein the amino acid comprises at least one substance selected from the group consisting of neurosis, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine and serine, May be D-coordination, L-coordination, or DL-coordination as appropriate.

In another embodiment, the millable milling matrix is selected from the group consisting of mannitol and sodium chloride, lactose monohydrate, anhydrous lactose, glucose, sucrose, trehalose, sorbitol, 1-O-alpha-D- glucopyranosyl- Malt), xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium Citrate, sodium ascorbate. But are not limited to, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sodium lauryl sulfate, ; PEG 6000, PEG 3000 Tween 80, Poloxamer 188, leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, , Where the amino acid may be in D, L, or DL configuration as appropriate depending on the application desired.

In another embodiment, the Millerbly pulverulent matrix comprises sucrose and at least one compound selected from the group consisting of sodium chloride, lactose monohydrate, anhydrous lactose, mannitol, glucose, trehalose, sorbitol, 1-O- alpha -D- glucopyranosyl- Malt), xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium But are not limited to, citrate, sodium ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, Lauryl sulfate, magnesium lauryl sulfate, PEG 6000, PEG 3000 Tween 80, Poloxamer 188, Wherein the amino acid comprises at least one substance selected from the group consisting of neurosis, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine and serine, May be D-coordination, L-coordination, or DL-coordination as appropriate.

In another embodiment, the Millerbly pulverulent matrix is selected from the group consisting of glucose and sodium chloride, lactose monohydrate, anhydrous lactose, mannitol, sucrose, trehalose, sorbitol, 1-O-alpha-D- glucopyranosyl- Malt), xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium But are not limited to, citrate, sodium ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, Lauryl sulfate, magnesium lauryl sulfate, PEG 6000, PEG 3000 Tween 80, Poloxamer 188, Wherein the amino acid comprises at least one substance selected from the group consisting of neurosis, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine and serine, May be D-coordination, L-coordination, or DL-coordination as appropriate.

In another embodiment, the millable milling matrix is selected from the group consisting of sodium chloride and anhydrous lactose, lactose monohydrate, mannitol, glucose, sucrose, trehalose, sorbitol, 1-O-alpha-D- glucopyranosyl- Malt), xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium But are not limited to, citrate, sodium ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, Lauryl sulfate, magnesium lauryl sulfate, PEG 6000, PEG 3000 Tween 80, Poloxamer 188, Wherein the amino acid comprises at least one substance selected from the group consisting of neurosis, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine and serine, May be D-coordination, L-coordination, or DL-coordination as appropriate.

In another embodiment, the Millerbly pulverulent matrix is selected from the group consisting of trehalose and sodium chloride, anhydrous lactose, lactose monohydrate, mannitol, glucose, sucrose, sorbitol, 1-O-alpha-D- glucopyranosyl- Malt), xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium But are not limited to, citrate, sodium ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, Lauryl sulfate, magnesium lauryl sulfate, PEG 6000, PEG 3000 Tween 80, Poloxamer 188, Wherein the amino acid is selected from the group consisting of an amino acid, an amino acid, an amino acid, an amino acid, an amino acid, an amino acid, an amino acid, an amino acid, It may be D-coordination, L-coordination, or DL-coordination as appropriate according to the application.

In another embodiment, the millable milling matrix is a single material or a mixture of two or more materials in any proportion. In another embodiment the substance is selected from the group consisting of sodium chloride, mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, But are not limited to, sucrose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, trehalose, inulin, isomalt or other sugar or polyol, aspartic acid, glutamic acid, sodium gluconate, maltodextrin, Tran, magnesium gluconate, peptides and proteins such as human serum albumin, organic salts such as sodium citrate and sodium ascorbate lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidylglycerol, dipalmitoyl phosphatidylethanolamine, dipalmitoyl phosphatidylinositol , Phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycine Glycerol, phosphatidylinositol, phosphatidylserine, or other phospholipids; Stearic acid and its derivatives or salts such as sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, magnesium stearate, calcium stearate, sodium stearate, lithium stearate; Solid state fatty acids such as palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives thereof including esters and salts; Lauric acid and its salts, such as sodium lauryl sulfate, magnesium lauryl sulfate; Triglycerides such as Dynsan 118 and Cutina HR; Gelatin, hypromellose; PEG 6000, PEG 3000 or other PEGS; Tween 80, Poloxamer 188; Amino acids such as aspartic acid, glutamic acid, leucine, L-leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, serine, phenylalanine lysine, - cysteine, where the amino acid may be in D, L or DL configuration as appropriate according to the application required and its derivatives, salts, solvates, hydrates and polymorphs; And peptides and polypeptides having a molecular weight of 0.25 to 1000 kDa.

In one embodiment, the millable milling matrix is selected from lactose (e. G., Lactose monohydrate), mannitol, glucose, sucrose, and xylitol.

In another embodiment, the milling matrix is harder than the pharmaceutical active, and thus can reduce the particle size of the active substance under dry milling conditions. Without wishing to be bound by any particular theory, it is believed that under the disclosed dry milling conditions, the millable milling matrix provides the advantage of smaller particles of the milling matrix produced under dry milling conditions that allow greater interaction with the pharmaceutical active agent . Without wishing to be bound by any particular theory, it is contemplated that the physical degradation (including, but not limited to, particle size reduction) of millable milling matrix provides the advantage of acting as a more effective diluent than a larger particle size milling matrix I think.

In another embodiment, the amount of the milling matrix relative to the amount of pharmaceutically active agent and the degree of physical degradation of the milling matrix are sufficient to inhibit re-aggregation of the particles of active material. In another embodiment, the amount of the milling matrix relative to the amount of pharmaceutically active agent and the degree of physical degradation of the milling matrix are sufficient to inhibit re-aggregation of particles of the active material in nanoparticulate form. In another aspect, the grinding matrix is generally prepared by a conventional milling process, except that, for example, the matrix is intentionally chosen to go through a mechanical-chemical reaction, e. G., Conversion to a free base or acid salt, Is not selected to be chemically reactive with the pharmaceutical active under the conditions. Without wishing to be bound by any particular theory, the pulverulent matrix will physically degrade under the disclosed dry milling conditions that facilitate the formation and preservation of microparticles of the pharmaceutically active agent with reduced particle size. The exact degree of degradation required will depend on the specific properties of the milling matrix and the pharmaceutically active agent, the ratio of the pharmaceutically active agent to the milling matrix, and the particle size distribution of the particles comprising the pharmaceutically active agent.

The physical properties of the milling matrix required to achieve the required dissolution depend on the precise milling conditions. For example, a lighter grinding matrix will degrade to a sufficient extent if it undergoes more severe dry milling conditions. The physical properties of the milling matrix associated with the extent to which the material is degraded under dry milling conditions include hardness, fracture properties as measured by index such as hardness, fracture toughness and embrittlement. A low hardness (typically less than 7 Mohs hardness) of the pharmaceutical active is desirable to ensure the fracture of the particles during processing, thereby producing complex microstructure during milling. Preferably, the hardness is less than 3 when determined using the Mohs hardness scale.

In another embodiment, the milling matrix has low abrasive properties. While not wishing to be bound by any particular theory, low abrasiveness is desirable for minimizing contamination of the milling chamber of the media mill and / or the mixture of pharmaceutical active agents in the milling matrix by the milling body. The indirect index of abrasiveness can be obtained by measuring the level of contaminants in the milling-base.

In another embodiment, the millable milling matrix has a low aggregation tendency during dry milling. Although it is difficult to quantify the aggregation tendency during milling objectively, subjective measurements can be obtained by observing the "caking" level of the milling chamber and the milling body of the milling chamber of the media mill as the dry milling progresses .

2. Milling preparation

In one aspect, the present invention is directed to the use of a milling aid in the disclosed method for making composite particles comprising a pharmaceutically active agent and a millable milling matrix. In another embodiment, the composite particles further comprise a milling aid. In another embodiment, a combination of milling aids or milling aids is used in the dry milling step. In another embodiment, the milling aid is added to the mixture of the pharmaceutically active agent and the millable milling matrix prior to completion of the dry milling step. In another embodiment, the milling aids are added prior to the completion of milling in a mill without a milling body.

In another embodiment, the milling aids are selected from surfactants, polymers, phospholipids, fatty acids or derivatives, stearic acid and derivatives thereof, and amino acids or derivatives.

In another embodiment, the milling aids are selected from the group consisting of lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidylethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, Sodium stearate, calcium stearate, sodium stearate, lithium stearate, palmitic acid, stearic acid, europic acid, behenic acid, sodium lauryl sulfate, magnesium stearate, magnesium stearate, Weil Sulfate; Dynsan 118, Cutina HR, aspartic acid, gelatin, glutamic acid, hiropromellose, PEG 6000, PEG 3000, Tween 80, Poloxamer 188, leucine, L-leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine , Aspartic acid, glutamic acid, cysteine, alanine, serine, phenylalanine lysine and N-acetyl-L-cysteine.

In another embodiment, the milling aid is selected from the group consisting of lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidylethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, Phospholipids, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, magnesium stearate, calcium stearate, sodium stearate, lithium stearate. Solid state fatty acids such as palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives thereof (such as esters and salts), lauric acid and its salts such as sodium lauryl sulfate, magnesium lauryl sulfate; Triglycerides such as Dynsan 118 and Cutina HR, aspartic acid, gelatin, glutamic acid, hiropromellose, PEG 6000, PEG 3000 or other PEGS, Tween 80, Poloxamer 188, amino acids such as leucine, isoleucine, lysine, valine, methionine, Wherein the amino acid may be in the D, L or DL configuration as appropriate according to the field of application required, N, N, N, N, N, -Acetyl-L-cysteine, and peptides and polypeptides having a molecular weight of 0.25 to 1000 kDa.

In one embodiment, the milling aid is selected from lecithin, phospholipids, polyvinylpyrrolidone, polyoxyethylene sorbate ester, polysorbate 80, polysorbate 20.

In one embodiment, the millable milling matrix is selected from lactose (e.g., lactose monohydrate), mannitol, glucose, sucrose, and xylitol.

In one embodiment, the millable milling matrix is selected from lactose (e.g., lactose monohydrate), mannitol, glucose, sucrose, and xylitol, and the milling aids include lecithin, phospholipids, polyvinylpyrrolidone, polyoxyethylene sorbate ester , Polysorbate 80, polysorbate 20.

3. Promotion preparation

In another embodiment, the accelerator is lecithin; But are not limited to, soybean lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phospholipid, sodium stearyl fumarate, Lactate, zinc stearate, magnesium stearate, calcium stearate, sodium stearate, and lithium stearate.

In another embodiment, the accelerator is selected from solid state fatty acids. In another embodiment, the solid-state fatty acids are selected from palmitic acid, stearic acid, erucic acid, and behenic acid, or derivatives thereof such as esters and salts. In another embodiment, the accelerator is selected from lauric acid and lauric acid salts. In another embodiment, the lauric acid salt is selected from sodium lauryl sulfate and magnesium lauryl sulfate. In another embodiment, the accelerator is triglyceride. In another embodiment, the triglyceride is selected from Dynsan 118 and Cutina HR.

In another embodiment, the promoter is an amino acid. In another embodiment, the amino acid is selected from the group consisting of aspartate, glutamic acid, leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, serine, , Or a pharmaceutically acceptable derivative, salt, solvate, hydrate, and polymorph thereof.

In another embodiment, the promoter is selected from peptides and polypeptides having a molecular weight of 0.25 to 1000 KDa. In another embodiment, the accelerator is selected from gelatin, hiromellose, PEG 6000, PEG 3000 or other PEGS, Tween 80, and Poloxamer 188.

4. Pharmacologically active agents

In one aspect, the invention provides a pharmaceutical composition comprising a compound selected from the group consisting of a vitamin, a pharmaceutically active substance, a biological agent, an amino acid, a protein, a peptide, a polypeptide, a nucleotide, an oligonucleotide, a vaccine, a monoclonal antibody, a nucleic acid, Solvates, hydrates, and fragrances thereof. In another embodiment, the pharmaceutically active agent is a substance used in the treatment of disorders in an animal. In another embodiment, the pharmaceutically active agent is used in the treatment of human disorders.

In another embodiment, the pharmaceutically active agent is an organic compound. In another embodiment, the pharmaceutically active agent is a substance that one of skill in the art desires to be delivered to the lungs by oral inhalation. In another embodiment, the pharmacologically active agent may also be a material for which one of ordinary skill in the art desires improved solubility characteristics. Examples of pharmaceutically active agents are provided below (additional embodiments).

C. Nanoparticles of pharmaceutical active agents

1. Determination of Particle Size of Pharmaceutical Active Agent

There are a wide range of techniques used to characterize the particle size distribution of materials. The technique chosen for material characterization will depend on the size of the material to be analyzed, the information required and the nature of the material to be determined. If the measured particle is less than 1 μm, it may be difficult to use any aerodynamic or dry powder measurement system. Instead, other conventional ensemble methods should be used. Such techniques are required because the active particles are typically less than 1 [mu] m in the present invention. Of these various methods, two types of measurements are most widely used. Photon correlation spectroscopy (PCS), also known as 'dynamic light scattering' (DLS), is commonly used for particle measurements with sizes less than 10 microns. Typically, these measurements yield a substantially hydrodynamic radius, which is often expressed as the average size of the water distribution. Another common particle size measurement method is laser diffraction, which is commonly used for particle size measurements from 100 nm to 2000 μm in particle size. This technique computes the volume distribution of a particular particle, which can be expressed using a predicate such as a median particle size or a percentage of particles smaller than a given size.

It will also be appreciated by those skilled in the art that almost all such techniques measure physical phenomena that are interpreted as representing particle size, rather than physically measuring particle size, such as measuring something with the particle. As part of the interpretation process, you can make some assumptions to make mathematical calculations. These assumptions convey considerable particle size, or results such as hydraulic radii.

Skilled artisans recognize that many different characterization techniques, such as photon correlation spectroscopy and laser diffraction, measure many different characteristics of a particle ensemble. As a result, several techniques will provide several answers to the question, "What is particle size?" In theory, it is possible to switch and compare the various parameters measured by each technique, but this is not practical for real world particle systems. As a result, the particle size used to illustrate the present invention can be given as two different sets of values, each of which is associated with two conventional measurement techniques, so that the measurement is made for a certain technique, Can be evaluated.

For measurements made using optical correlated equipment, or equivalent methods known in the art, the term "number average particle size" is defined as the average particle diameter determined on a number basis.

For measurements made using laser diffraction equipment, or equivalent methods known in the art, the term "median particle size" is defined as the median particle diameter determined based on a particular particle volume basis. If the term median is used, it is understood that it accounts for the particle size that divides the population in half so that 50% of the population is larger or smaller than this size. Median particle size is often described as D50, D (0.50) or D [0.5] or similar. As used herein, D50, D (0.50) or D [0.5] or the like should be taken to mean "median particle size".

The term " Dx of particle size distribution "refers to the xth percentile of the distribution on a particle volume basis; Thus, D90 refers to the 90th percentile, D95 refers to the 95th percentile, and so on. Taking D90 as an example, this can often be described as D (0.90) or D [0.9] or the like. For median particle size and Dx, the capital letter D or the lowercase letter d are interchangeable and have the same meaning. Another way to quantify the particle size distribution is the volume weighted average (D4,3). D4,3 is defined as the sum of the squares of the diameters divided by the sum of the squares of the diameters.

Another commonly used way to describe the particle size distribution measured by laser diffraction, or equivalent methods known in the art, is to describe how few percent of the distribution is smaller or larger than the nominal size. The term "less than percent", also referred to as "% <", is defined as the volume percentage of the particle size distribution smaller than the nominal size - for example, <1000 nm. The term "percentage of excess", also referred to as "%>", is defined as the volume percentage of the particle size distribution greater than the nominal size - for example,> 1000 nm.

The particle size used to describe the present invention should mean the particle size measured just prior to use. For example, the particle size is measured two months after the material undergoes the milling method of the present invention. In a preferred form, the particle size is selected from the following: 1 day after milling, 2 days after milling, 5 days after milling, 1 month after milling, 2 months after milling, 3 months after milling, 4 months after milling, 5 months after milling, Month, one year after milling, two years after milling, and five years after milling.

The particle size can easily be measured in many materials that go through the process of the present invention. If the active material has a poor water solubility and the matrix to which it is milled has a good water solubility, the powder can be simply dispersed in an aqueous solvent. In such a scenario, the matrix dissolves leaving the active material dispersed in the solvent. Such suspensions may be measured by techniques such as PCS or laser diffraction.

Suitable methods for accurate particle size measurement are outlined below where the active material has a significant water solubility or the matrix has a low solubility in aqueous dispersions.

In situations where an insoluble matrix such as microcrystalline cellulose interferes with the measurement of the active material, a separation technique such as filtration or centrifugation may be used to separate the insoluble matrix from the active material particles. Other ancillary techniques will also be required to determine if any active material is removed by the separation technique, and so this can be considered.

If the active substance is too soluble in water, other solvents may be evaluated for the determination of the particle size. If the solvent can be found to be a poor solvent for the active material but a good solvent for the matrix, the measurement will be relatively straightforward. If it is difficult to find such a solvent, another approach would be an ensemble measurement of the matrix and the active material in both insoluble solvents (e.g., iso-octane). The powder will then be measured in another solvent in which the active substance is soluble but the matrix is not. Thus, by measuring the matrix particle size and measuring the size of the matrix and the active material together, an understanding of the particle size of the active material can be obtained. Another approach to measuring active particles with moderate to high water solubility is to measure the size of the active material in a saturated solution.

In some situations, image analysis can be used to obtain information on the particle size distribution of the active material. Suitable imaging techniques may include transmission electron microscopy (TEM), scanning electron microscopy (SEM), optical microscopy and confocal microscopy. In addition to these standard techniques, some additional techniques may be required to be used in parallel for active material and matrix particle differentiation. Possible techniques depending on the composition of the relevant material may be elemental analysis, Raman spectroscopy, FTIR spectroscopy or fluorescence spectroscopy.

In some other cases, nanoparticles of the pharmaceutically active agent are formed, but there is a small amount of flocculation or crosslinking. Therefore, when analyzed by ensemble techniques such as laser diffraction, they appear to be larger particles. As one of skill in the pharmacy arts will understand, the key to such materials is product performance, not what size the device can represent. Thus, if the particle dimensions are indeed nano-sized and the particles have a high surface area available, they will act as in- vivo nanoparticles.

In the present invention, the required core aspect of the pharmaceutically active agent is sufficiently small such that even after the composite particle size is reduced to the size for inhalation, it is uniformly distributed throughout the composite material. If an ensemble particle size method such as laser diffraction can not be used, other techniques and values will be required for material characterization. Some examples of such methods include, but are not limited to:

1. image analysis of SEM micrographs of the composition;

2. SEM or TEM microscopy combined with elemental or spectroscopic analysis;

3. SEM or TEM microscopy method optionally combined with elemental or spectroscopic analysis for the sections of composite particles prepared in resin;

4. AFM analysis combined with Raman microscopy;

5. Image analysis of SEM micrographs of the active material after the matrix material has been washed; And

6. Measure the specific surface area (SSA) of the active material after the matrix material has been washed. Certain diameters can be calculated from SSA, or SSA itself can be used as a quantitative predicate. There may be a need to dry the active material after washing the matrix. It is important to preserve the high surface area during the cleaning and drying process. A possible way to do this would be spray drying of the active material.

2. Pharmaceutical Active Particle Size

In one aspect, the invention relates to a composite particle comprising a millable milling matrix and a pharmaceutically active agent, wherein the pharmaceutical active is a particle dispersed in a composite particle. In another embodiment, the sub-particle of the pharmaceutically active agent in the composite particle is a nanoparticle. In another embodiment, the sub-particles of the pharmaceutically active agent in the composite particle produced by the disclosed method have a particle size of less than 1000 nm. In another embodiment, the sub-particles of the pharmaceutically active agent in the composite particles produced by the disclosed method have a particle size of less than 500 nm. In another embodiment, the sub-particle of the pharmaceutically active agent is crystalline. In another embodiment, the sub-particles of the pharmaceutically active agent in the composite particle have an average particle size of about 50 nm to about 1000 nm.

In yet another embodiment, the sub-particles of the pharmaceutically active agent in the composite particle are determined on the basis of the volume of the particles and can be about 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, And a median particle size below the selected size from 100 nm. In another embodiment, the median particle size of the pharmaceutically active agent is greater than about 25 nm.

In another embodiment, the percentage of particles of the pharmaceutically active agent based on particle volume is selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the percentages are about 1000 nm, 800, 600, 400 or less than 200 nm or from 1000 to 500 nm, from 900 to 400 nm, from 800 to 300 nm. In another embodiment, the percentage of particles of the pharmaceutically active material on a particle volume basis is selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the percentage is about 500 nm. In another embodiment, the percentage of particles of the pharmaceutically active agent based on particle volume is selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the percentage is less than about 300 nm . In yet another embodiment, the percentage of particles of the pharmaceutically active agent based on particle volume is selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the percentage is less than about 200 nm .

In another embodiment, the Dx (e.g., D ₅₀ ) of the particle size distribution of the pharmaceutical active agent, measured on a particle volume basis, is greater _than 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, , 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm; Where x is about 90 or more.

3. Dissolution profile

The disclosed method produces a pharmaceutically active agent having an improved dissolution profile. There is an improved dissolution can provide improved bioavailability of the active agent within the pharmaceutical vivo. In one embodiment, an improved dissolution profile is observed in vitro . In another embodiment, an improved dissolution profile is observed in vivo by observation of an improved bioavailability profile. Standard methods for determining the in vitro dissolution profile are available in the art. A suitable method for determining an improved in vitro dissolution profile may include determining the concentration of a sample material in a solution over a period of time and comparing the result from the sample material with a control sample. The observation that the maximum solution concentration for the sample material can be achieved in a shorter time than the control sample can indicate that the sample material has an improved dissolution profile if it meets statistical significance.

Typically, all formulations are placed in the dissolution equipment for testing during a typical dissolution profile measurement. Such procedures are used in the assessment of the dissolution profile of oral preparations. In the case of oral medicines, this is appropriate, because all the active substances in the formulation are absorbed into the gastrointestinal tract, which has the opportunity to be absorbed by the body. In contrast, not all of the active particles of the inhaled formulation can effectively reach the lungs where the active agent may act locally or be systemically absorbed. To more accurately assess what in vivo dissolution profiles can be obtained from in vitro measurements, the formulation must first be separated into components that will reach the lungs and components that do not. Only components that can reach the lung should be evaluated. Son et al. [ Dissolution Technologies , 17 (2), 6-13 (2010)] proved such a method. The inhaled formulation was run through an NGI device equipped with an extra filter to collect the fraction of particles with MMAD suitable for deposition in the lungs. These particle fractions were then tested in standard dissolution equipment.

In another embodiment, the dissolution profile of the disclosed composite particles, inhalable complex, or composition for inhalation is determined as described above and can be compared to conventional inhalation compositions. Conventional formulations are defined as inhalation formulations prepared using jet milled active materials and carrier excipients such as lactose.

Standard methods for determining improved in vivo substance solubility profiles are available in the art. A suitable method for determining an improved dissolution profile in humans may be to measure the rate of absorption of the active substance by measuring the plasma concentration of the sample compound over time after delivery of the dose and comparing the results from the sample compound to the control have. An observation that the maximum plasma concentration for the sample compound was achieved within a shorter time than the control will indicate that the sample compound has improved bioavailability and improved dissolution profile (assuming statistical significance). Preferably, when observed ex vivo, an improved dissolution profile is observed in dissolution media similar to body fluids found in the lungs. Suitable methods for quantifying the concentration of compounds in in vitro samples or in vivo samples are widely available in the art. Suitable methods may include the use of spectroscopy or radioisotope labels.

D. Composite Particle Characteristics

1. Particle size of composite particles

a. How to decide

One measure that can be used to characterize the particle size of the composite is the aerodynamic particle size. Aerodynamic particle size as used herein refers to volume or mass particle size measurements based on the aerodynamic characteristics of the particles being measured. It is known to those skilled in the art that the aerodynamic diameter D (a) of an individual particle is related to the density p and the Stokes diameter D (s) according to the following equation: D (a) = D (s) ^1/2 . The diameter of the particles is the diameter of the sphere having the same final settling velocity as the particles to be measured. Thus, the aerodynamic size of a particle is a measure of how it behaves when aerosolized. The aerodynamic particle size can be measured using a commercially available device, e.g. Aerosizer LD or ^{Model 3321 Aerodynamic Particle Sizer ® (TSI} Incorporated, Shoreview, MN 55126 USA) or similar device is known to a person skilled in the art as a commercial.

Another measurement that can be used to determine the size of the composite is laser diffraction. These measurements are generally divided into wet and dry methods. The wet method uses a solvent such as iso-octane or isopar G that does not dissolve the matrix and will not also dissolve the active material on nearly all pharmaceutically active substances. The composite is first dispersed in a solvent, sometimes dispersed with a dispersing aid such as lecithin, and then measured using a standard wet laser diffraction measurement cell. Laser diffraction instruments for performing such measurements are known in the art, some of which are Malvern Mastersizers, Sympatec, and Microtrac. Dry powder laser diffraction measurements use the same principle as the wet process, except that in this case air flow is used to disperse and transport the particles through the laser beam. An example of a measuring instrument that performs this is a RODOS dispersing unit used with a Scirocco measuring cell for use with a Malvern Mastersizer, a Turbotrac dispersing unit with a Microtrac device, or a Sympatec laser diffractometer. In such a measuring instrument, compressed air can be used for powder dispersion to determine the primary particle size of the composite.

Another approach to dry powder laser diffraction measurements is to use a passive dispersion method. When these measurements are performed, there is no dispersion cell in the instrument itself. Instead, the powder is packaged in a suction device attached to the measuring device. A limited airflow then passes through the device to allow the powder to exit the device (after any dispersion that the device can deliver) and pass the laser beam. The airflow used in the passive laser diffraction is typically in the range of 20-100 L / min. This range of airflow is used because it simulates airflow during human inhalation. In other words, passing air through the device and dispersing the powder in a manner similar to that that occurs when a patient uses the device means that the powder properties are also similar to those that occur during patient use. The particle size distribution of the powder dispersed in this manner is obtained and is similar to that inhaled by the patient. Laser diffraction instruments for performing passive laser diffraction measurements are known in the art, some of which are Sympatec instruments with Malvern Spraytec or INHALER modules.

All three laser diffraction techniques, wet, dry powder and passive, measure the diffraction pattern produced by the ensemble of particles within the same physical property: the measuring area. The instrument then computes a particle size distribution (on a volume or mass basis) of a particular particle size. The particle size distribution will typically feature a median particle size (D [50]), a volume weighted average value (D [4,3]), or a 90th percentile (D [90]).

Another approach for measuring aerodynamic particle size is to use an apparatus that directly measures the aerodynamic particle size by flow through differently sized grids. Examples of such devices are impactors and dust collectors in which particles will be retained on multiple stages depending on their aerodynamic size. The particles smaller than any given stage will continue to another stage until the stage reaches if the size is greater than the cutoff. The inspection can then be used to establish a mass balance across a series of stages with different size cutoffs to establish a particle size distribution. The evaluation is typically an assessment of the active substance present in the formulation. Since the active particles in conventional inhalation formulations are discontinuous particles, the particle size distribution of the test and the subsequent is the distribution of active particles from the formulation going to the test device. In contrast, the disclosed complex particles have pharmaceutical actives particles uniformly distributed throughout the complex particles, so that they are, in effect, marker probes that enable to determine the mass distribution of the composite particles throughout the impactor or dust collector stage. The aerodynamic particle size distribution thus calculated is actually the distribution of the composite particles in the formulation. Examples of impactors and dust collectors are CI, MSLI and NGI.

It is important to keep in mind that these measuring devices do not measure the aerodynamic particle size of the entire ensemble of particles (such as Aeroszier LD or Model 3321 Aerodynamic Particle Sizer ^® ). This is because before the powder enters the impactor / dust collector, it must first go through an induction port (often referred to as a throat) to remove a portion of the powder from the airflow and some devices through the pre-separator. By design, the induction port and pre-separator remove larger particles from the distribution. This means that the measurements do not report the size distribution of the entire powder sample but the aerodynamic particle size of the material through the induction port and the pre-separator. This impactor / dust collector is designed in this manner to simulate what happens when a dry powder formulation is inhaled into the mouth. During the oral inhalation process, the larger particles will have greater momentum and will hit the back of the throat while particles within the correct size range will flow down towards the lungs. For this reason, the impactor / measurements from the precipitator to provide an optimal in vitro indicator of in vivo performance.

It is still necessary and important to know and measure the particle size distribution of the whole powder because it provides a knowledge of the potential for powder formulations once combined with the inhalation device. Measurements such as laser diffraction and flight time measurements are easier and therefore useful for providing tools for optimization and rapid quality control analysis. From this information provided by the mass distribution over the various stages of the impactor / collector, the following can be determined: Mass Median Aerodynamic Diameter (MMAD), Geometric Standard Deviation (GSD) and FPF. These parameters are described in more detail below.

b. Composite particle characteristics

In one aspect, the present invention relates to a composite particle comprising a millable milling matrix and a pharmaceutically active agent having suitable particle size characteristics. In another embodiment, the disclosed composite particles of a millable milling matrix and a pharmaceutically active agent have a median particle size of from about 1 to about 20 micrometers. In another embodiment, the disclosed composite particles comprising a millable milling matrix and a pharmaceutically active agent have a median particle size of less than about 10 占 퐉. In another embodiment, the disclosed composite particles comprising a millable milling matrix and a pharmaceutically active agent have a median particle size of about 5 占 퐉 or less. In another embodiment, the disclosed composite particles comprising a millable milling matrix and a pharmaceutically active agent have a median particle size of about 4 占 퐉 or less. In another embodiment, the disclosed composite particles comprising a millable milling matrix and a pharmaceutically active agent have a particle size of less than about 3 占 퐉.

In another embodiment, the composite particles have a median particle size of about 10,000 nm or less. In another embodiment, the composite particles are determined on a particle volume basis and have a D90 of 15,000 nm or less. In another embodiment, the particles for inhalation complexes are determined on a particle volume basis and have a D90 of at least 2000 nm. In another embodiment, the composite particles have a volume weighted average value D4,3 of about 10,000 nm or less. In another embodiment, the composite particles have a bulk weighted average (D4,3) of at least 1000 nm.

In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent are determined based on the volume of the particles and are selected from the group consisting of 10,000 nm, 8000 nm, 6000 nm, 5000 nm, 4500 nm, 4000 nm, 3500 nm, 32500 nm, Selected from the group consisting of UV, UV, IR, IR, IR, IR, IR, IR, IR, Size median particle size. In another embodiment, the disclosed composite particles comprising a millable milling matrix and a pharmaceutically active agent have a median particle size of greater than or equal to 1000 nm. In another embodiment, the median particle size is measured by dry powder laser diffraction, passive dry powder laser diffraction or wet laser diffraction. In another embodiment, the median particle size is measured by passive laser diffraction.

In yet another embodiment, the composite particle comprising a millable milling matrix and a pharmaceutically active agent may be at least one selected from the group consisting of 10,000 nm, 8000 nm, 6000 nm, 5000 nm, 4500 nm, 4000 nm, 3500 nm, 3250 nm, a volume weighted average value D4 of not more than a size selected from the following: nm, 2700 nm, 2600 nm, 2500 nm, 2400 nm, 2300 nm, 2200 nm, 2100 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, , 3). In another embodiment, the composite particles comprising a millable smoothed matrix and a pharmaceutically active agent have a bulk weighted average (D4,3) of at least about 1000 nm. In another embodiment, (D4,3) is measured by dry powder laser diffraction, passive dry powder laser diffraction or wet laser diffraction. In another embodiment, (D4,3) is measured by passive laser diffraction.

In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent are determined on the basis of the particle volume and have a particle size distribution such as 15,000 nm, 12,000 nm, 11,000 nm, 10,000 nm, 9000 nm, 8000 nm, 7000 nm, 5000 nm, 4000 nm, and 3000 nm, respectively. In another embodiment, the disclosed composite particles comprising a millable smoothed matrix and a pharmaceutically active agent have a D90 of greater than or equal to about 2000 nm. In another embodiment, D90 is measured by dry powder laser diffraction, passive dry powder laser diffraction or wet laser diffraction. In another embodiment, D90 is measured by passive laser diffraction.

In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent have a particle size in the range of 15,000 nm, 12,000 nm, 11,000 nm, 10,000 nm, 9000 nm, 8000 nm, 7000 nm, 6000 nm, 5000 nm, lt; RTI ID = 0.0 &gt; nm. &lt; / RTI &gt; In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent have an average particle size of at least about 1000 nm. In another embodiment, the average particle size is measured by a flight time instrument.

2. Content uniformity

a. How to decide

In this context, the content uniformity is a measure of how evenly the pharmaceutical active (s) are distributed throughout the formulation. Content uniformity is important for the accurate delivery of pharmaceutical active agents from the dry powder formulation to the lungs. However, in some current commercial formulations, a small amount of the pharmacologically active agent is delivered from the suction device to the lungs at a level of 0.02 mg in a 5 mg dose of powder. For optimal therapeutic and clinical value, the content uniformity in the powder for inhalation should be very accurate and highly repeatable.

Typically, the content uniformity is determined by examining multiple samples by HPLC or similar techniques and determining the concentration of the pharmaceutical active in each sample. In bulk powder samples, content uniformity can be measured from three or more samples. When the powder is filled into a packaging container such as a hard capsule or a foil blister pack, the appropriate number of packages will be evaluated to determine content uniformity (e.g., typically 10 randomly selected from a greater number) . If a package such as a capsule is examined to determine the content uniformity of the substance, the test shall be modified with respect to the total weight of the powder in each package. One common measure for content uniformity is the average concentration of a compound (e.g., batch or lot) or the percentage deviation of each sample from a known concentration. For quality control, the content uniformity specification will provide that the sample does not have a deviation greater than a defined percentage. The second conventional measure is the RSD of the sample test from the mean (e.g. RSD from the mean of the sample being analyzed, or alternatively RSD from the known or set concentration of the bulk material).

The term "separation" refers to the stratification of the particle size distribution of a material such as a powder or blend. This can be caused by any physical process, but typically occurs when the powder or formulation undergoes a flow, e.g., during transport, handling, storage, and mixing, or other movement, and in a hopper or other processing facility do. The powder or combination in an undivided state will have a uniform particle size distribution across the entire powder or blend so that any sample taken from any portion of the bag or container holding the powder (e.g., top, middle, bottom) Size distribution. In a powder that has undergone separation, a portion of the powder will have larger particles than the other portion and some will have smaller particles than the other portions of the powder. In powders with segregation, samples taken from various positions (e.g., stomach, middle, bottom) in the bag or container holding the powder will typically exhibit slight differences in particle size distribution. For testing the properties of the powders, forced separation can be used to check for any content uniformity changes after separation. An example of forced separation is to put the powder into a tube and turn the tube at a slightly inclined angle for a long time to separate the large and small particles.

b. Composite particle characteristics

In one aspect, the invention relates to a composite particle comprising a millable milling matrix and a pharmaceutically active agent having suitable content uniformity properties. In another embodiment, the content uniformity of the solid pharmaceutical active agent dispersed in the composite particles has a percentage difference of less than about 5.0% from the average content. In another embodiment, the uniformity of the pharmacologically active agent throughout the formulation is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 3.0% % And the following percentages differ from the average content. In another embodiment, the content uniformity after separation of the pharmaceutical active agent throughout the formulation is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 3.0% And 5.0%. &Lt; / RTI &gt; In another embodiment, the uniformity of the pharmacologically active agent throughout the formulation is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 3.0% %, &Lt; / RTI &gt; In another embodiment, the content uniformity of the pharmaceutically active agent throughout the formulation has a percent relative standard deviation (RSD) of about 5.0% or less. In another embodiment, the content uniformity after separation of the pharmaceutical active agent throughout the formulation is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 3.0% And 5.0%. &Lt; / RTI &gt;

3. Surface roughness

a. How to decide

The shape, texture and roughness of individual particles for their association with particles and their distribution are important particle properties that affect some key properties of the particles used in the inhalation composition, including fluidity, cohesion, and solubility characteristics . In one embodiment, the surface roughness can be characterized by parameters such as surface roughness (RSA), root-mean-square root (Rrms), and median adhesion (F [50]). The meaning and use of these terms are described above. Briefly, RSA can be determined by measuring the surface area calculated from the spherical equivalent size determined by laser diffraction and the specific surface area (SSA) with nitrogen absorption along with the BET isotherm. In another embodiment, the laser diffraction method used is powder laser diffraction. Both Rrms and F [50] Adi, et al. ( Langmuir , 2008, 34: 11307-11312 and Pharm. Sci ., 2008, 35: 12-18, respectively) Rrms is also described by Adi et al. ( Langmuir , ibid ). &Lt; / RTI &gt;

b. Composite particle characteristics

In one aspect, the invention relates to a composite particle comprising a millable milling matrix and a pharmaceutically active agent having suitable surface roughness characteristics. In another embodiment, the composite particles have a roughness ratio by surface area of at least about a ratio of about 1.1; Wherein the specific surface area is measured using nitrogen absorption; Where the surface area is calculated from the spherical equivalent size determined by dry powder laser diffraction. In another embodiment, the composite particles have Rrms above a height selected from about 15 nm, wherein Rrms is measured using atomic force microscopy. In another embodiment, the composite particles have Rrms above a height selected from about 15 nm, wherein Rrma is measured using a white light interference measurement. In another embodiment, the composite particles have a median adhesion (F [50]) of less than about 150 nN as measured by atomic force microscopy.

In another embodiment, the composite particles comprising a millable milling matrix and a pharmaceutically active agent may be present in an amount ranging from 15 nM, 30 nM, 50 nM, 75 nM, 100 nM, 125 nM, 150 nM, 175 nM, nm, 275 nm, 300 nm, 325 nm, 350 nm, 375 nm and 400 nm. In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent have a particle size of 1.1, 1.2, 1.3, 1.4, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, And 5.0. &Lt; / RTI &gt; In another embodiment, the composite particles comprising a millable smoothed matrix and a pharmaceutically active agent may have a particle size ranging from 150 nN, 125 nN, 100 nN, 80 nN, 70 nN, 60 nN, 50 nN, 40 nN, 30 nN, 25 nN, 20 50 [N], 15 nN, 10 nN and 5 nN.

4. Aggregation and powder flow

a. How to decide

In order to prepare a commercially available dry powder formulation, the powder flow should be suitable for accurate and precise delivery of small amounts of powder. Typically, the amount of powder delivered and sucked into the dry powder inhaler typically ranges from about 1 to about 20 mg. For preparations with high loadings, this amount may be more, for example from about 20 to about 200 mg. Powders comprising pharmaceutical active agents and carrier excipients should have flow properties that allow for accurate and precise delivery of a fixed amount of powder. Depending on the type of device used for powder delivery, the method used to measure this accuracy and precision will vary. When the powder is delivered to the solid storage device, the device itself will be used for powder delivery of aliquots for each inhalation. In other devices, some sort of packaging container is used to pre-charge a single volume into a suitable container for operation in the device. Examples of such packaging containers are hard gelatin capsules, rigid HMPC capsules, foil blister strips or foil blistering. The filling of such a packaging container is carried out using an automatic or semi-automatic dispenser to fill the capsule or foil blister. The accuracy and precision with which such a dispenser can deliver a given volume of powder is a measure of the powder flow, i.e., good powder flow results in better accuracy and repeatability. In contrast, poor powder flow causes variability in the amount of powder delivered to the capsule or foil blister. The variability of the powder dispensed from an automatic or semi-automatic filing machine can be quantified in a number of ways. For example, the weight of several samples dispensed into a packaging container can be determined, and then the percentage at which each sample weight differs from the average weight delivered is calculated. Alternatively, the variability of the dispensed powder can be determined from the weighing of the various samples dispensed into the packaging container, and the weight difference can be calculated from the delivered average weight as a representation of the RSD of the sample number.

b. Composite particle characteristics

In one aspect, the invention is directed to composite particles comprising a millable milling matrix and a pharmaceutically active agent having suitable cohesive and powder flow properties. In yet another embodiment, the weight of the composite particles deviates from the average weight distributed during dispensing from an automated or semi-automated filing machine by a percentage of less than about 10%. In another embodiment, the number of samples measured when the relative standard deviation (RSD) from the average weight is greater than 50 samples delivered automatically or semi-automatically is about 10% or less.

In another embodiment, the weight dispensed from the automated filing machine of the powder comprising the composite particles is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5% Wherein the composite particles have a percent difference of less than or equal to a percentage selected from%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, and 10.0% l wherein the composite particles comprise a millable milling matrix and a pharmaceutically active agent do. In another embodiment, the target weight of the powder comprising the composite particles to be dispensed for such a test is 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 75 mg, 100 mg, 150 mg and 200 mg. In another embodiment, the number of dispensed samples to be metered for such a test is selected from 3, 5, 10, 15, 20, 25, 30, 50, In another embodiment, a semi-automatic filing machine is used to dispense powder instead of an automatic filing machine.

In another embodiment, the weight dispensed from the automated filing machine of the powder comprising the composite particles is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0% Wherein the composite particles have a RSD from a distributed average weight that is less than or equal to a percentage selected from 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% and 10.0%, wherein the composite particles comprise a millable milling matrix and a pharmaceutically active agent . In another embodiment, the target weight of the powder comprising the composite particles to be dispensed for such a test is 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg , 75 mg, 100 mg, 150 mg and 200 mg. The number of dispensed samples to be weighed for such a test is selected from the group consisting of 3, 5, 10, 15, 20, 25, 30, 50, In another embodiment, the number of dispensed samples to be metered for such a test is selected from 3, 5, 10, 15, 20, 25, 30, 50, In another embodiment, a semi-automatic filing machine is used to dispense powder instead of an automatic filing machine.

5. Stability

a. How to decide

An important feature of dry powder inhalation formulations is the stability of formulation performance over time during storage. Typically, parameters such as emission capacity (ED), FPF and MMAD are determined as a function of time. These parameters need to be relatively stable over a reasonable period of time that corresponds to the typical cycle of manufacture, storage, sale, and end-use consumer use. Otherwise, the formulation is unlikely to be commercially available. The period in which these parameters are kept within an acceptable use standard is typically referred to as the validity period. Conventional inhaled formulations often have stability problems that are commonly thought to arise from particle-particle interaction changes in the formulation. While not wishing to be bound by any particular theory, it is believed that the disclosed composite particles simplify the range and nature of particle-particle interactions, and thus, the disclosed compositions comprising composite particles have the same amount of active material and excipient And thus it is expected to have improved stability characteristics. Stability studies are typically performed by placing a sample of material in an environmental chamber having specific temperature and humidity conditions. At the specified time, the sample is removed and inspected for a given characteristic or parameter of interest. For the disclosed composite particles, the sample will be examined for ED, FPF, MMAD, or any other parameter described herein. Typical studies were 1, 3, 7, 14, 21, and 28 days; And will include sample analyzes of 2, 3, 4, 6, 9, 12, 18 and 24 months.

b. Composite particle characteristics

In one aspect, the invention relates to a composite particle comprising a millable milling matrix and a pharmaceutically active agent having suitable stability characteristics. In another embodiment, the stability of the composite particles comprising the millable milling matrix and the pharmaceutically active agent is determined by the following conditions: 25 占 폚 , 30 占 폚, 35 占 폚, 40 占 폚, 25 占 폚 / 60% relative humidity, 30 占 폚 / 65% ℃ / 75% relative humidity. In another embodiment, the stability of the composite particles comprising the millable milling matrix and the pharmaceutically active agent is measured after storage for a period selected from 1 month, 3 months, 6 months, 9 months, 12 months, 18 months and 2 years. In another embodiment, the stability of the composite particles comprising the millable milling matrix and the pharmaceutically active agent is determined by determining the value of the specific properties at the start of storage, and the percentage change from the nature of the storage start may be 0.1%, 0.2% 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% %, 15%, 17.5% and 20%. In another embodiment, specific properties determined for stability are selected from ED, MMAD, FPF, and particle size.

6. Aerodynamic characteristics (ED, FPF, GSD, and MMAD)

a. How to decide

Transfer of the powder capacity from the dry powder inhaler is less complete. A number of parameters are used to describe the amount of powder delivered to (or expected to be delivered to) the device lung. FPF is defined as the fraction of pharmaceutical active having an aerodynamic diameter of from about 4 to less than about 6 [mu] m. MMAD is defined as an aerodynamic diameter in which 50% of the particles by mass are larger and 50% smaller. Another parameter useful in these particular property discussions is the geometric standard deviation (GSD), which is a measure of the diffusion of the aerodynamic particle size distribution. This is typically calculated using the formula: GSD = (d84 / d16) ^1/2 . For the parameters ED, FPF, GSD and MMAD, the value depends on the device used to perform the measurement. For example, ED, FPF, GSD, and MMAD may be determined using an MSLI with an induction port, a CI with an induction port and a pre-separator, or an NGI with an induction port and a pre-separator.

In one aspect, the invention relates to composite particles wherein the parameters of ED, FPF, GSD, and MMAD are determined using NGI with an induction port and a pre-separator. In another embodiment, the composite particle parameters of ED, FPF, GSD and MMAD are determined using an apparatus selected from NGI with induction ports and CI with induction port and pre-separator, or NGI with induction port and pre-separator . It should be noted that, for the disclosed composite particles, the pharmaceutically active agent aggregates uniformly into the composite particles, and therefore the ED, FPF, GSD and MMAD for the pharmaceutical active are also these specific indicators for the composite particles.

The ED provides an indication of delivery of the drug formulation from a suitable inhaler device after an ignition or dispersion event. More specifically, for dry powder formulations, the ED is a measure of the percentage of powder exiting the unit dose package and exiting the mouthpiece of the inhaler device. The ED is defined as the fraction of the total available volume in the device delivered by the inhaler device. The ED is empirically determined by placing it in a single dose of dry powder, typically in unit dosage form, then in a suitable dry powder inhaler that operates and disperses the powder. The total amount of powder found to have left the unit is then measured and compared to the nominal capacity. This measurement can be made when the impactor / dust collector test is performed on the powder. The consistency of the ED is important, so multiple capacities must be measured and the consistency between capacities calculated. One way to measure this is the RSD from the average discharge capacity typically given in percent RSD (% RSD).

FPF is one of the most important predictors of in vivo performance for dry powder formulations and device combinations. As noted above, the FPF is the fraction for the dose delivered, unless otherwise specified, where ED is defined as the fraction of the total available dose in the device delivered by the inhaler device, which is often expressed as a percentage of the total dose. In some cases, the FPF for the total recovery capacity (TRD) is specified and appears as "FPF (TRD) &quot;. The total recovered capacity is the sum of the discharge capacity and the capacity remaining in the device and / or capacity packaging container. A further additional interest parameter for complex particles comprising two or more pharmaceutically active agents is the MMAD uniformity ratio and the FPF uniformity ratio. Both of these are defined and discussed above.

b. Composite particle characteristics

In one aspect, the present invention relates to a composite particle comprising a millable milling matrix and a pharmaceutically active agent having suitable aerodynamic properties. In another embodiment, the composite particles can be delivered from a dry powder inhaler and provided an aerosol having an FPF of at least about 10% of the pharmacologically active agent release, when analyzed using NGI with an induction port and a pre-separator . In another embodiment, the composite particles are delivered from a dry powder inhaler and analyzed using a NGI with an induction port and a pre-separator, wherein the relative standard deviation (RSD) of the FPF at a release dose of less than about 10% Lt; RTI ID = 0.0 &gt; aerosol &lt; / RTI &gt; In another embodiment, the composite particles are delivered from a dry powder inhaler and can be analyzed using an NGI with an induction port and a pre-separator to provide an aerosol having an FPF of greater than about 30% of the total recovered dose of the pharmaceutical active agent have.

In another embodiment, the composite particles are delivered from a dry powder inhaler and analyzed using a NGI with an induction port and a pre-separator to provide a median aerodynamic diameter (MMAD) of the composite particles from about 1 [mu] m to about 10 [mu] m May provide an aerosol. In another embodiment, the mass median aerodynamic diameter (MMAD) is from about 1 [mu] m to about 7 [mu] m. In another embodiment, the MMAD is from about 1.5 [mu] m to about 5 [mu] m. In another embodiment, the MMAD is from about 2 [mu] m to about 5 [mu] m. In another embodiment, the MMAD is from about 2 [mu] m to about 4 [mu] m.

In another embodiment, the composite particles are delivered from a dry powder inhaler and analyzed using NGI to provide a median aerodynamic diameter (MMAD) of the composite particles of about 1 [mu] m to about 10 [mu] m and a minimum of about 10% 0.0 &gt; FPF &lt; / RTI &gt; In another embodiment, the composite particles are delivered from a dry powder inhaler and can provide an aerosol having an ED of greater than about 70% at the time of analysis using NGI with an induction port and a pre-separator. In another embodiment, the composite particles are sprayed from a dry powder inhaler with an aerosol having an emission capacity of at least about 10% RSD at the time of determination for at least three samples analyzed using NGI with an induction port and a pre- Can be provided.

In another embodiment, composite particles comprising a millable milling matrix and a pharmaceutically active agent are measured using an NGI with an MSLI with an induction port, a CI with an induction port and a pre-separator, or with an induction port and a pre-separator ED, FPF, and GSD MMAD. In another embodiment, composite particles comprising a millable milling matrix and a pharmaceutically active agent have ED, FPF, GSD MMAD measured using NGI with a USP induction port and a pre-separator.

In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent are present in an amount ranging from 70%, 75%, 80%, 85%, 87.5%, 90%, 92.5%, 95%, 96% % &Lt; / RTI &gt; and 99%. In another embodiment, the composite particles comprising the Millerbly pulverulent matrix and the pharmaceutically active agent are present in an amount of 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0% % RSD of a set of three or more EDs below a percentage selected from%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% and 10.0%. In another embodiment, the ED determined for the pharmaceutical active is the same or about the same as for the composite particle. In another embodiment, the pharmaceutically active agent is uniformly aggregated in the disclosed composite particle, and thus the ED determined for the pharmaceutical active agent is also an indicator of ED for the composite particle.

In another embodiment, the composite particles comprising Millerbly pulverulent matrix and the pharmaceutically active agent have a particle size of 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, the MMF has an MMAD of less than or equal to a size selected from the group consisting of 0.1 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm and 6.0 μm. In another embodiment, the composite particles comprising the Millerbly pulverulent matrix and the pharmaceutically active agent are present in an amount of 10%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60% %, 75%, 80%, 85% and 90%. In another embodiment, the composite particles comprising the Millerbly pulverulent matrix and the pharmaceutically active agent are present in an amount of 10%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60% %, 75%, 80%, 85% and 90% of the FPF (TRD). In another embodiment, the composite particles comprising the Millerbly pulverulent matrix and the pharmaceutically active agent are present in an amount of 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0% % RSD of at least three measurements of FPF or FPF (TRD) below a percentage selected from%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% and 10.0%. In one embodiment, the FPF is about 50% -60% and the MMAD is 2 to 4 占 퐉 (e.g., 2.2 to 3.8 占 퐉, 2.4 to 3.6 占 퐉, 2.4 to 3.4 占 퐉, 2.5 to 3.1 占 퐉, or 2.6 to 3.0 占 퐉. In another embodiment, the FPF or FPF (TRD) determined for the pharmaceutical active is FPF or FPF (TRD) that is the same or about the same as for the composite particle. In another embodiment, the pharmaceutically active agent uniformly flocculates And thus the FPF or FPF (TRD) determined for the pharmacologically active agent is also an indicator of the FPF or FPF (TRD) for the composite particle.

In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent have a particle size of about 10,000 nm, 8000 nm, 6000 nm, 5000 nm, 4500 nm, 4000 nm, 3500 nm, 3250 nm, Has a MMAD of less than or equal to a selected size from 2800 nm, 2700 nm, 2600 nm, 2500 nm, 2400 nm, 2300 nm, 2200 nm, 2100 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm and 1500 nm. In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent have an MMAD of greater than about 1,000 nm.

In another embodiment, the composite particles comprising the millable milling matrix and the pharmaceutically active agent have a particle size of 4, 3.5, 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, &Lt; RTI ID = 0.0 &gt; GSD &lt; / RTI &gt;

In another embodiment, the composite particles are delivered from a dry powder inhaler and analyzed using NGI with an induction port and a pre-separator, wherein the ratio of the fine particles of the first pharmaceutical active agent and the second pharmaceutical active agent .

In another embodiment, the composite particles are delivered from a dry powder inhaler and have an MMAD uniformity ratio of less than or equal to about 1.2, as analyzed by NGI with an induction port and a pre-separator, wherein each of the first and second pharmaceutical active agents Are evaluated and used for MMAD calculation for composite particles, respectively.

In another embodiment, the composite particles comprising the millable milling matrix and the at least two pharmaceutically active agents have a particle size of about 1.002, 1.005, 1.0075, 1.01, 1.0125, 1.015, 1.0175, 1.02, 1.03, 1.04, 1.05, 1.075, 1.02, 1.05 , 1.075, 1.1, 1.125, 1.15 and 1.2. In another embodiment, the composite particles comprising the millable milling matrix and the at least two pharmaceutically active agents have a particle size of about 1.002, 1.005, 1.0075, 1.01, 1.0125, 1.015, 1.0175, 1.02, 1.03, 1.04, 1.05, 1.075, 1.02, 1.05 , 1.075, 1.1, 1.125, 1.15 and 1.2.

E. INHALATION COMPOSITION

In one aspect, the invention relates to a composition for inhalation of a pharmaceutically active composite particle prepared by a method comprising the steps of: (a) providing composite particles of a millable milling matrix and a solid pharmaceutical active, Wherein the pharmaceutically active agent in the composite particle has an average particle size of from about 50 nm to about 3 占 퐉; And (b) milling the composite particles in a mill without a milling body for a period of time sufficient to produce composite particles of a pulverulent matrix and solid pharmaceutical active agent having an effective aerodynamic particle size of from about 1 [mu] m to about 20 [mu] m.

In another aspect, the invention is directed to a pharmaceutical active composition for inhalation comprising a plurality of composite particles of a millable milling matrix and a solid pharmaceutical active, wherein the composite particles of the milling matrix and the solid pharmaceutical active are about 1 [mu] m To about 20 [mu] m, and the pharmaceutically active agent in the composite particle has an average particle size of from about 50 nm to about 3 [mu] m.

F. Pharmaceuticals

1. Manufacture of medicines

In one aspect, the invention is directed to the manufacture of a medicament comprising the disclosed composite particles comprising a pharmaceutically active agent and a millable milling matrix. In another embodiment, the medicament further comprises one or more of each of the other ingredients conventionally used in the manufacture of pharmaceutically acceptable carriers, milling aids, accelerators, pharmaceutically acceptable excipients, or pharmaceutically acceptable inhalation compositions As shown in FIG.

In another embodiment, the medicament may be formulated in a suitable device for administration by oral ingestion. The actual dosage level of the pharmaceutical active in the medicament of the present invention may vary depending on the nature of the pharmaceutical active material. In another embodiment, the dosage level will vary due to differences in therapeutically effective amounts when the agent comprises the disclosed complex particles. In another embodiment, agents comprising the disclosed composite particles are required to have a therapeutically effective dose with improved efficacy with less dosage.

In another embodiment, the disclosed composite particles may be combined with another pharmaceutical active agent material, or even with the same pharmaceutical active agent material, in a pharmaceutical. In another embodiment, the agent may have different release characteristics-an earlier release from a pharmaceutically active agent material, and a later release from a larger average-size pharmaceutical activator material.

a. accelerant

In another embodiment, the accelerator is lecithin; But are not limited to, soybean lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phospholipid, sodium stearyl fumarate, Lactate, zinc stearate, magnesium stearate, calcium stearate, sodium stearate, and lithium stearate.

In another embodiment, the accelerator is selected from solid state fatty acids. In another embodiment, the solid-state fatty acids are selected from palmitic acid, stearic acid, erucic acid, and behenic acid, or derivatives thereof such as esters and salts. In another embodiment, the accelerator is selected from lauric acid and lauric acid salts. In another embodiment, the lauric acid salt is selected from sodium lauryl sulfate and magnesium lauryl sulfate. In another embodiment, the accelerator is triglyceride. In another embodiment, the triglyceride is selected from Dynsan 118 and Cutina HR.

In another embodiment, the promoter is an amino acid. In another embodiment, the amino acid is selected from the group consisting of aspartate, glutamic acid, leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, serine, , Or a pharmaceutically acceptable derivative, salt, solvate, hydrate, and polymorph thereof.

In another embodiment, the promoter is selected from peptides and polypeptides having a molecular weight of 0.25 to 1000 KDa. In another embodiment, the accelerator is selected from gelatin, hiromellose, PEG 6000, PEG 3000 or other PEGS, Tween 80, and Poloxamer 188.

b. Carrier excipient

In another embodiment, the carrier excipient is selected from the group consisting of mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, Maltose, sorbose, cellobiose, sorbose, trehalose, inulin, and isomalt. In another embodiment, the carrier excipient is a sugar or a polyol. In another embodiment, the carrier excipient is lactose or mannitol. In another embodiment, the carrier excipient is lactose monohydrate.

In another embodiment, the diameter of the carrier-excipient particles is from about 50 [mu] m to about 1000 [mu] m. In another embodiment, the diameter of the carrier-excipient particles is from about 60 [mu] m to about 250 [mu] m. In another embodiment, the diameter of the carrier-excipient particles is from about 90 [mu] m to about 250 [mu] m.

2. Use of medicines

Therapeutic uses of agents comprising the disclosed complex particles, inhaled complexes, and the disclosed composite particles include, but are not limited to, pain relief, antiinflammation, antiinfection, migraine, asthma, COPD and other disorders requiring a pharmacologically active agent to be administered with high bioavailability . In another embodiment, the pharmacologically active agent has an optimal effect when topically delivered to the lungs. Alternatively, there is a therapeutic use in which optimal clinical benefit is achieved with rapid bioavailability of the pharmaceutical active, e. G., Relief of pain. In another embodiment, agents comprising the disclosed composite particles are used in the treatment of pain disorders. In another embodiment, the pain disorder is selected from neuropathic, analgesic, acute, chronic, and disease-specific pathways (e.g., pain associated with osteoarthritis or fibromyalgia). In another embodiment, an analgesic, such as a cyclooxygenase inhibitor, such as an aspirin or an NSAID, may be prepared as a medicament according to the present invention.

In another embodiment, agents comprising the disclosed composite particles can also be used for the treatment of ophthalmic disorders. In other words, the pharmaceutical active may be formulated for administration to the eye as an aqueous suspension, or gel, in physiological saline. In another embodiment, the pharmaceutical active may be prepared in powder form for administration via the nose for rapid central nervous system transmission.

In another embodiment, agents comprising the disclosed composite particles can be used for the treatment of cardiovascular diseases. In another embodiment, the treated cardiovascular disease is angina. In another embodiment, the pharmaceutically active agent is molshipmin. The clinical benefits and adverse effects profile of morpholine can be improved by delivery to the lungs. While not wishing to be bound by any particular theory, such improvements may be due to improved bioavailability.

In another embodiment, the agents comprising the disclosed composite particles can be used for the treatment of hair loss, sexual dysfunction, or psoriasis skin.

G. How to treat patients

1. Patient Care

In one aspect, the invention is directed to a method of treating a patient in need of treatment of a disorder comprising administering an effective amount of a pharmaceutically active composition for inhalation comprising a plurality of composite particles of a millable milling matrix and a solid pharmaceutical active, Wherein the composite particles have an effective aerodynamic particle size from about 1 [mu] m to about 20 [mu] m; The pharmaceutically active agent in the composite particle has an average particle size of about 50 nm to about 3 [mu] m.

In another embodiment, the treatment is prophylaxis. In another embodiment, the patient is diagnosed with a disorder prior to administration.

In another embodiment, the disorder to be treated is selected from chronic obstructive pulmonary disease, acute asthma, chronic asthma, severe asthma, allergic asthma, acute respiratory distress syndrome, infant respiratory distress syndrome, reversible airway disease, and cystic fibrosis.

In another embodiment, the disorder being treated is an infection. In another embodiment, the infection is selected from bacterial, fungal, and viral. In another embodiment, the infection is a bacterial infection. In another embodiment, the infection is a viral infection. In another embodiment, the infection is a fungal infection.

In another embodiment, the disorder being treated is a pain disorder. In another embodiment, the pain disorder is selected from neuropathic, analgesic, acute, chronic, and disease-specific pathways (e.g., pain associated with osteoarthritis or fibromyalgia).

In another embodiment, the disorder being treated is selected from cystic fibrosis, tuberculosis, pneumonia, severe acute respiratory syndrome, infection, pre-occlusion, tuberculosis, pulmonary hypertension, pulmonary edema, and pulmonary pneumonia. In another embodiment, the disorder being treated is selected from blindness, hair loss, sexual dysfunction, and cardiovascular disease. In another embodiment, the cardiovascular disease is angina pectoris.

2. Inhalation delivery

Dry powder formulations of active pharmaceutical ingredients (including combinations of active materials and excipients) for oral inhalation are important tools for the delivery of medicaments. A common use has been in the delivery of topically acting pharmaceutical substances, for example, asthma medications delivered to the lungs. This delivery path has also become more important for telegraph delivery. Two of the important parameters for the inhaled dry powder formulation are the particle size and fluidity of the powder. The powder in the device used by the patient needs to be well flowed so that a powdered formulation of uniform and consistent capacity leaves the device. If the powder flow is poor, the powder may remain in the device or stick to the device when it is dispensed. Thus ensuring that the particle size powder (and active material) of the powder is delivered to the required absorption zone.

Typical particle size measurements as used in the determination of dry powder formulations are the mass median aerodynamic diameter (MMAD). As noted above, the aerodynamic diameter, MMAD, is 50% larger and 50% smaller in mass. An aerodynamic particle size measurement method including the Anderson Cascade Impactor or the New Generation Impactor is described above. Alternatively, particle size measurements such as the median particle size measured by laser diffraction dry powder analysis are also useful. However, MMAD is a preferred measure for inhaled agents because it better approximates the aerodynamic properties of the lungs. In another embodiment, the inhaled formulation has a MMAD of less than about 10 [mu] m. In another embodiment, the inhaled formulation has an MMAD of less than about 5 [mu] m. In another embodiment, the inhaled formulation preferably has a median particle size of less than about 10 [mu] m, wherein the dry powder size determination is determined by laser diffraction.

3. Packaging and equipment

The powder must be packed in a suitable device to deliver the powder to the lungs by mouth suction. The device should be suitable for aerosolizing the powder during the inhalation process. In yet another aspect, the apparatus should allow a single dose of the package, which is packaged in an individual package, to be inserted into the apparatus prior to delivery. In another aspect, the apparatus has a storage container for delivering multiple doses. In another aspect, an apparatus having two or more discrete doses of powder packaged in a powdered individual package and assembled or inserted into the apparatus allows delivery of multiple doses. Appropriate devices may be multivalent or disposable.

In another embodiment, the device is selected from the group consisting of 3M Conix (TM) 1 DPI (3M), 3M Conix (TM) 2 DPI (3M), 3MTaper DPI (3M), Acu-Breathe Vectura), Cricket ™ Inhaler (Mannkind), Dreamboat ™ (Mannkind), Duohaler (Vectura), Easyhaler ^® (Orion), Flowcaps ^® (Hovione), Genuair ^® (Almirall Sofotec), Gen - X ^® (Cambridge Consultants), GyroHaler (Vectura), Manta Multi Dose (Manta), Manta Single Dose (Manta), MicroDose DPI (MicroDose Therapeutx), Next ™ (Chiesi Farmaceutici), Novolizer ^® (Meda / Almirall Sofotec), Prohaler ™ (Valois), SkyeHaler ™ Skene Pharma), Smartinhaler (Nexus 6), Solis (TM) (Oriel Therapeutics / Sandoz), Sun DPI (Sun Pharmaceuticals / Cambridge Consultants), TAIFUN ^® (Akela Pharma / Focus Inhalation), Twin Caps Groningen University), Xcaps (Hovione), Spinhaler (Aventis), Rotahaler (GlaxoSmithKline), Inhalator (Boehringer-Ingeheim), Cyclohaler (Pharmachemie), Handihaler (Boehringer- , Aerolizer (Novartis), FlowCaps (Hovione), TwinCaps (Hovione), Turbohaler (Astra Zeneca), Diskhaler (GlaxoSmithKline), Diskus / Accuhaler (GlaxoSmithKline), Aerohaler (Boehringer-Ingeheim), Easyhaler ), Pulvinal (Chiesi), Novolizer (ASTA), MAGhaler (Boehringer-Ingeheim), Taifun (LAB Pharma), Eclipse (Aventis), Clickhaler (Innoveta Biomed), Asmanex Twisthaler , AIR (Alkermes), Turbospin (PH & T), CRC-749 (Pfizer), Omnihaler (Innoveta Biomeds Ltd), Actispire (Britania), DirectHaler (Direct- Haler), JAGO (SkyPharma) Cyclovent (Pharmachemie), Dispohler (AC Pharma). Microhaler (Harris Pharmaceutical), Technohaler ( Innoveta Biomed Ltd), Spiros (Dura), Bulkhaler (Asta Medica), Miat-Haler (MiatSpA), Monodose Inhaler (MiatSpA), Acu-Breath (Respirics), Swinghaler ® (Otsuka Pharmaceutical Co Ltd., Pfeiffer (Pfeiffer GmbH), Certihaler (Novartis Pharma / Skye Pharma), Otsuka DPI / Breath actuated (Otsuka Pharmaceutical Co. Ltd), Flexihaler (Astra Zeneca) , And devices that are similar or generic copies of these devices.

In another embodiment, the device is assembled or inserted into a packaging container that carries powder ready to be dispensed by the device just prior to the inhalation process. For example, hard capsules are used as packaging. In another embodiment, the hard capsule used as packaging is made of gelatin or HMPC. In another embodiment, the capsule has a size selected from the group consisting of size 4, size 3, size 2, size 1, and size 0. In another embodiment, the capsules are further packaged in individual blister packs. In another embodiment, a blister pack is formed from an aluminum foil laminate at the top and bottom. Special packaging containers are used in devices containing multiple doses. For example, the packaging container used may comprise a multiple blister pack, a small blister pack formed from aluminum foil laminates at the top and bottom. In some instances, it is preferred that the blister pack is in the form of a strip of individual blisters. In another embodiment, the foil blister is formed from a disc or ring.

H. Experiments

1. Substance

The following materials were used in the examples: Active pharmaceutical ingredient (salbutamol) was supplied from commercial suppliers, lactose from DMV-Fonterra, and lecithin (USP grade) from Spectrum chemicals. Ventolin Rotocaps (200 μg salbutamol as salbutamol sulfate) was obtained as a commercial supplier. Unless otherwise specified, when the material in the composition is given as a percentage, it is weight percent (% w / w) unless otherwise specified.

2. General method

a. Attritor type mill

Dry-milling experiments were conducted using a 1S Union Process attritor mill with a 1.5 gallon grinding chamber. The milling media consisted of 20 kg of 3/8 "stainless steel balls. A total of 1 kg of powder was milled for each batch. After the mill was loaded through the loading port and the milling media was initially added, The milling process was carried out with a jacket cooled to 13-16 ° C and a shaft rotating at 400 rpm When the milling was complete the milled powder was discharged from the mill at 77 rpm through the bottom discharge port.

b. Air jet milling:

Two air jet milling conditions were used.

10 inch air jet milling was performed in a 10 "Spiral Jet Mill (Powdersize Inc) at a feed rate of 10 kg / hr. 500-1000 grams of powder was fed through each mill for each sample.

Four inch air jet milling was performed at 4 "Spiral Jet Mill (Powdersize Inc) at variable feed rates and pressures. 50-40 grams of powder was fed through the mill for each sample.

c. Laser diffraction

Particle size distribution (PSD) was determined using a Malvern Mastersizer 2000. A Malvern Hydro 2000S pump unit was used for wet (aqueous) measurement of the active material. A Scirocco 2000 measuring unit was used for the dry particle size measurement of the composite.

The following settings were used for wet measurements: measurement time: 12 seconds, measurement cycle: 3. The final result was generated by averaging three measurements. Samples were measured by adding dry powder to saturated salbutamol containing ~ 0.03% PVP. A maximum of two minutes of ultrasonic treatment was applied within the measurement cell prior to the measurement. The refractive index of the active material was set to 1.56 with absorption at 0.01.

For dry measurements, a pressure of 3-3.5 bar was used for the measurement. The refractive index of lactose was used for the analysis (1.35 as absorbance at 0.01).

Another laser diffraction measurement of the composite was measured using isoparG as the solvent. This was done on a Microtrac S3000 instrument using a 10 second up time. The refractive index of the composite was set at 1.51 and the solvent was set at 1.42.

d. Flight time measurement:

Flight time measurements were taken on a TSI Aerosizer with Aerodisperser set to medium shear force and feed rate. De-agglomeration was set to normal and the pin was being vibrated. Particle size statistics are volume distributions.

e. Aerodynamic particle size distribution:

Aerodynamic particle size distribution was performed in a Next Generation Pharmaceutical Impactor equipped with a stainless steel collection cup, a pre-separator and a USP induction port. The test was carried out with a total flow of 4 L with a pressure drop of 4 kPa up to 100 L / min. The actual flow was approximately 98-100 L / min. It was used as obtained from commercial Ventolin Rotocaps. If another powder (~ 20 mg) is filled into Size 3 HPMC inhalation capsules or Harro Hoefliger The size 3 HPMC inhalation capsule was mechanically filled (~ 24.5 mg) using an Omnidose Drumfiller (see section g for setup). All capsules were tested in a Monodose Inhaler. HPLC analysis was used for the assay of the activity.

f. Powder uniformity

10 samples were taken from the bulk formulation at locations throughout the sample. They were then examined by HPLC and expressed as% RSD for 10 samples. Tests by HPLC for some batches were also measured.

g. Automatic Powder Dispensing

Harro Hoefliger The Omnidose Drumfiller was used for powder dosing to determine the accuracy and precision of powder dispensing. The dispenser was set to 35 cycle / min, 500 mbar product vacuum, 300 mbar dispense pressure with 2 agitator rotations (180% speed) and 2 shots per cavity. The powder was filled into a stainless steel thimble to accurately weigh the mass of the dispensed powder.

h. Scanning Electron Microscopy (SEM)

SEM was measured on a Zeiss 1555 VPSEM. Before imaging, a powder sample was applied to the carbon tab on the SEM stub and coated with 3-5 nm platinum.

3. Preparation of composite particles having 10% salbutamol in lactose monohydrate

a. Dry-milling of 10% salbutamol in lactose monohydrate:

The batches (labeled 1A, B, C, and D) of 10% salbutamol in lactose monohydrate containing 1% (w / w) lecithin were dry-milled to 1 kg scale for 15 minutes. The particle size of the pharmaceutically active agent was measured and the data are shown in Table 1. Particle size data of complex particles including salbutamol and lactose are also shown in Table 1.

b. Air jet milling:

The material from batch 1A-D was subjected to air jet-milling in 10 inch setup at four different pressures, 7.24 Bar (batch 2A), 4.83 Bar (batch 2B), 3.45 Bar (batch 2C) and 1.72 Bar . The particle size of the composite particles is shown in Table 2 and the particle size was measured by wet laser diffraction using Isopar ^TM G as a dry laser or solvent, as indicated. The particle size of the pharmaceutical active, salbutamol, was determined after air jet-milling for batch 2A-D using wet laser diffraction and is shown in Table 3. The particle size of the air jet-milled composite particles was determined by flight time measurement and the data are shown in Table 4. [

4. Preparation of composite particles having 1% salbutamol in lactose monohydrate

a. Dry-milling of 1% salbutamol in lactose monohydrate:

Another batch (labeled with 3A) was dry-milled at 1 kg scale for 20 minutes using 1% salbutamol and 1% lecithin, using lactose monohydrate as a millable milling matrix. Particle size data, including complex particles comprising lysate butyramol and lactose in batch 3A,

b. Air jet milling:

The material from batch 3A was air jet-milled in a 10 inch setup at 4.83 Bar (batch 3B). The particle size of the composite particles of batch 3B is shown in Table 6 and the particle size was measured by wet laser diffraction using a dry laser or Isopar ^TM G as solvent, as indicated. The particle size of the pharmaceutical active, salbutamol, was determined after air jet-milling for batch 3B using wet laser diffraction. The particle size is shown in Table 7. The particle size of the air jet-milled composite particles was determined by flight time measurement and the data are shown in Table 8. [

c. Next Generation Impactor Measurement

Ventolin Rotacaps and Powder from batch 3B were all evaluated via NGI. Three capsules were analyzed for each sample (Ventolin Rotocap or Batch 3B as indicated, where each pharmacologically active agent was salbutamol). After 6 months of testing of the batch 3B bulk powder stored at ambient conditions, it was divided into two groups. One flock was used to manually fill additional capsules for NGI testing (3 capsules). The other flock was filled with capsules using an Omindose Drumfiller. These capsules (3 capsules tested) were tested 8 months after the initial NGI test of batch 3B. In Tables 9 and 10, the average of the three measurements and the relative standard deviation (RSD,%) between these three measurements are shown. The data presented in Tables 9 and 10 show the mass of salbutamol in each of the various components of the test equipment and stage determined by testing for salbutamol. The table shows the size cutoff for each stage (assuming a flow of 100 L / min). The total recovery capacity (TRD) is the sum of all materials in the equipment. ED is the total of the substances found in the induction port to the MOF (filter), ie, all but the capsule and residue in the device. The fine particle capacity (FPD) is the amount of material calculated below the aerodynamic diameter of 5 μm. Calculations for FPD were performed using the Copley Inhaler Testing Data Analysis Software (Copley Scientific Limited, Nottingham, UK).

The data from Tables 9 and 10 were then used to estimate the release capacity as MMAD, the percentage of TRD, the percentage of particles below 5 μm for ED and TRD, also as MMAD. This data is shown in Table 11, which shows the release capacity as a percentage of TRD, FPF for ED and TRD as indicated, and MMAD calculated from NGI measurements.

The data in this example show that the oral inhalation preparation produced by the present invention is superior to the conventionally prepared formulation (Ventolin Rotacaps). The MMAD for both samples was found to be the same and therefore a direct comparison is indeed plausible. The first core excellence is 10% greater discharge capacity in batch 3B as less powder remains in the device after operation. The core excellence is the FPF, where batch 3B also has twice the amount of active material in the particle size range appropriate for inhalation. The data also shows that the transfer of capacity for batch 3B is more consistent and bibliographic uniform. The percent RSD for each of the stages for the Ventolin sample is at least twice that measured for batch 3B. This indicates that batch 3B has a much more consistent particle size distribution per dose compared to the Ventolin sample. This is important for the patient because the exact size of the particle will determine the part of the lung to which the active is delivered. The bioavailability and efficacy of the active substance depends on the portion of the lungs in which the particles settle, so that the variability in where the active material is deposited will cause variability in the therapeutic effect.

The data for batch 3B, measured 6 and 8 months later, also shows a slight change from the initial test, demonstrating that the invention described herein is capable of producing formulations with stable performance over time. 3B placed in 8 months was also filled in capsules using automated filing machine. Thus, the fact that there is a slight change in the aerodynamic properties also demonstrates that the powders prepared according to the present invention can be successfully filled using automation equipment without disturbing the powder properties.

d. Powder uniformity

The powder uniformity of batch 3B was measured and the data are shown in Table 12. [ The data indicate that the formulation has good uniformity even with such low active loading. It should also be noted that batch 3A was manufactured in Australia and transported to the United States for jet milling to batch 3B and then the sample was shipped to another facility for uniformity testing. The fact that the content uniformity is maintained at a high level is strong evidence for the excellent uniformity properties of this material.

e. Powder fluidity

Samples of batch 3B over 6 months were distributed from Harro Hoefliger Omnidose Drumfiller. A set of 60 24.5 mg shots of powder was dispensed. The average weight for this set was 24.53 mg. The minimum fill weight was 23.58 mg. The maximum filling weight was 25.37 mg. The relative standard deviation (% RSD) was 1.70.

5. Preparation of composite particles having ipratropium bromide and salbutamol sulfate in lactose monohydrate

a. Dry-milling of ipratropium bromide and salbutamol sulfate in lactose monohydrate:

(4A, B, C, and D) of various% of ipratropium bromide and salbutamol sulfate in lactose monohydrate having 1% w / w lecithin were diluted to 1 kg scale for 20 minutes Dry-milled. The percentages of the two active compounds in each batch are shown in Table 13. Particle size data of composite particles comprising ipratropium bromide, salbutamol sulfate and lactose are also shown in Table 13. [

b. Air jet milling:

Materials from each of batches 4A-D were split in two and air jet-milled in a 4 inch setup under two different conditions. The lower energy states were a pressure of 3.45 Bar and a relative feed rate of 385-425 and the higher energy states were a pressure of 4.14-4.48 Bar and a relative feed rate of 220-275. The relative feed rate of 220 is a target feed rate of 350 grams / hour. Details of how each batch was milled are shown in Table 14. The particle size of the composite particles is shown in Table 15 and the particle size was measured by wet laser diffraction using a dry laser or Isopar ^TM G as solvent, as indicated.

c. Powder uniformity

The content of active material and the powder uniformity in batch 4E-L were determined by HPLC and the data are shown in Table 16. The data indicate that the powder has an accurate content and excellent uniformity even with very little active water loading. It should be noted that these batches were dry milled in Australia, shipped to the United States for jet milling and then transported back to Australia for inspection and uniformity testing. The fact that the content uniformity is maintained at a high level despite this extensive transport is strong evidence for the excellent uniformity properties of this material.

d. Scanning Electron Microscopy (SEM)

A SEM photograph of one sample (4J) was taken and is shown in Figures 1-2. Figure 1 shows at an enlargement of 10,000X and shows an overview of composite size and shape. The image clearly shows that the particles have an irregular shape and a primary particle size of 1-5 microns. FIG. 2 is a photograph showing that at a high magnification, composite particles are aggregates of active particles and matrix of 200 nm or less. The figure also shows that the composite particles have high surface roughness on the nanometer scale.

It will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

I. Other Embodiments

In another embodiment, the pharmaceutical active is selected from the group consisting of alpha 1 antitrypsin, beclomethasone, budesonide, calcitonin, cyclosonide, ciprofloxacin, clarithromycin, clinafloxacin, clock factin, colistin, , Erythromycin, erythropoietin (EPO), erythropoietin, erythropoietin, erythropoietin, erythromycin, ergotamine, ), Ethaminophylline, factor IX, fenfiride, fentanyl, fluoxylin, fluney solid, flurisolid, flulythromycin, fluticasone, formoterol, glycopyrrolate, guanifenesin, hydrocortisone, (IGF), interferon alpha, interferon beta, interferon gamma, ipratropium, ipratropium, revricidimip, levocetirizine, insulin, (LMWH), mabuterol, marshilukast, mesystane, metaproterenol, methicillin, miliveterol, mometasone, montelukast, muscarinic acetyl Choline receptor antagonist and beta 2 adrenoceptor double agonist (MABA), allodasterol, omalizumab, oxitropium, oxystripylline, pyruvateol, polymyxin B, pranlukast, procatartrol, proinsulin, Pyruvate, pyruvate, rifampicin, salbutamol, salmeterol, ceratologist, theophylline, tobramycin, tofilmilast, tulobuterol, vancomycin, vasopressin, bilanterol, x-ray contrast agent, xylomethazoline Pyruvic acid, pyruvic acid, pyruvic acid, pyruvic acid, pyruvic acid, pyruvic acid, pyruvic acid, gireuton, or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof.

In another embodiment, the pharmaceutical active is insulin. In another embodiment, the insulin is selected from the group consisting of recombinant insulin, insulin purified from mammals, substituted insulin, pro-insulin, semi-synthetic insulin, synthetic insulin, or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof Is selected. In another embodiment, the insulin is selected from the group consisting of human recombinant insulin, insulin regular, insulin aspart, insulin aspartic protamine, insulin detemir, insulin glargine, insulin glutamine, insulin isoprene, insulin lispro, or a pharmaceutically acceptable salt thereof , Solvates, hydrates, or polymorphs thereof.

In another embodiment, the pharmaceutical active is selected from the group consisting of beclomethasone, budesonide, cyclosonide, ciprofloxacin, cholestin, dihydroergotamine, formoterol, fluticasone, insulin, ipratropium, Masticin B, rifampicin, salbutamol, salmeterol, tobramycin, or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof.

In another embodiment, the pharmaceutical active agent is selected from the group consisting of AZD1419, AZD1981, AZD3199, AZD5069, AZD5423, AZD8683, AZD9164, AZD9668, GSK1325756, GSK159802, GSK2190915, GSK2245840, GSK256066, GSK573719, GSK610677, GSK681323, GSK961081, GW870086, PF184, PF3526299, PF3635659 , PF3893787, PF4191834, PF4764793, PF610355, TD4208, and TD5959.

In another embodiment, the composite particles further comprise a second pharmaceutically active agent to produce composite particles of the matrix having the solid pharmaceutical active agent dispersed in the matrix and the second pharmaceutical active agent. In another embodiment, the first and second pharmaceutical active agents are fluticasone and salmeterol; Budesonide and formate; Cyclosonide and formometrol; Beclomethasone and formate; Fluticasone and formate; Mometasone and formate; Ipratropium and salbutamol; Fluticasone and bilanerol; Mometasone and formate; Indacaterol and mometasone; Apomoterol and cyclosonide; Indacaterol and thiotropeum; Acridinium and formometrol; Farotropeum and bilanetrol; Formoterol and glycopyrrolate; GSK573719 and bilanetrolipentate; Or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof.

In another embodiment, the pharmaceutically active agent is selected from known classes of drugs. In another embodiment, the known class of drugs include 5-hydroxytryptamine (5-HT) receptor antagonists, 5-lipoxygenase (5-LO) -activated protein (FLAP) inhibitors,? 2 adrenergic receptor A combination of a glucocorticoid receptor (GR) agonist, a combination of a? 2 adrenergic receptor (ADRB2) agonist and a leukotriene D4 (LTD4) receptor antagonist, a? 2 adrenergic receptor (ADRB2) agonist and a mu opioid receptor antagonist and a muscarinic M1 receptor antagonist, a combination of a? 2 adrenergic receptor (ADRB2) agonist and a muscarinic M3 receptor antagonist, a combination of a? 2 adrenergic receptor (ADRB2) agonist and a muscarinic receptor antagonist, a combination of a glucocorticoid receptor (GR) agonist and a histamine H1 receptor antagonist, a glucocorticoid receptor GR) agonist and a leukotriene D4 (LTD4) receptor antagonist, a histamine H1 receptor antagonist and A combination of a human leukocyte elastase (HLE) inhibitor and a protease 3 (PRTN3) inhibitor, an adenosine A1 receptor (ADORA1) antagonist, an adenosine A2B receptor (ADORA2B) antagonist, adenosine An antidepressant, an antiinflammatory agent, an anti-arrhythmic agent, an anti-asthmatic agent, an antibacterial agent, an antiinflammatory agent, an antiinflammatory agent, Antihistamines, antihypertensive agents, anti-inflammatory agents, anti-malarial agents, anti-migraine agents, anti-inflammatory agents, anti-inflammatory agents, anti-inflammatory agents, anti-inflammatory agents, anti-inflammatory agents, An antimicrobial agent, an anti-narcotic agent, an anti-obesity drug, an antioxidant, an anti-parasitic agent, an anti-parkinsonian agent (dopamine antagonist) Beta-adrenergic receptor (ADRB2) agonist, beta2 adrenergic receptor (ADRB2) agonist, beta-adrenoceptor blocker, (CTGF) inhibitor, CC chemokine receptor 3 (CCR3) antagonist, chemokine (CC motif) receptor 4 &lt; RTI ID = 0.0 &gt; (CCl4) antagonists, cell surface antigens and hypoglycemic agents, central nervous system stimulants, chemoattractant receptor-homologous molecules expressed in TH2 cell (CRTH2) antagonists, chloride channel type 2 (ClC-2) activators, C- (CD28) receptor antagonists, complement inhibitors, contrast media, contrast agents, corticosteroids, cough suppressants (e. G., Expectorants and &lt; (Antiparkinson), ELA2 inhibitor, ELA2 inhibitor, IL-2 inhibitor, and the like), COX-2 inhibitors, Croman, CXC chemokine receptor 2 (CXCR2) antagonists, cytokine receptors, diagnostic imaging agents, diuretics, (GST) activators, growth factors, growth supplements, hemostatic agents, antioxidants, antioxidants, antioxidants, E-selectin inhibitors, L-selectin inhibitors, P-selectin inhibitors, glucocorticoid receptor Hormone, human leukocyte elastase (HLE) inhibitor, hypnotic, sedative, hypoglycemic agent, immunoglobulin E (IgE) receptor antagonist, histamine H1 receptor antagonist, Inhibitors of the kappa light polypeptide gene in immunoglobulins, immunomodulators, immunosuppressants, infectious agents, inflammatory mediators, B-cell / kinase gamma (IKBKG) Inhibitors of the kappa light polypeptide gene enhancer in the B-cell / kinase beta (IKBKB) inhibitor, inhibitors of the kappa light polypeptide gene enhancer in the B-cell / kinase epithalone (IKBKE) IL-1 receptor antagonist, interleukin-4 (IL-4) receptor antagonist, interleukin-5 (IL-5) receptor antagonist, interferon, interleukin 13 (IL13) inhibitor, interleukin 4 receptor (IL4R) mRNA inhibitor, Inhibitors of the kappa light polypeptide gene enhancer in inhibitors of B-cell / kinase beta (IKBKB), leukotriene C4 (LTC4) receptors in inhibitors of interleukin-9 (IL-9) Receptor antagonist, leukotriene D4 (LTD4) receptor antagonist, leukotriene D4 (LTD4) receptor antagonist / leukotriene E4 (LTE4) receptor antagonist, leukotriene C4 Receptor antagonist, leukotriene receptor antagonist, leukotriene, lipid modulating agent, L-selectin inhibitor, lymphotoxin A (LTA) inhibitor, lymphotoxin A (LTA) inhibitor / tumor necrosis factor- , Matrix metalloproteinase (MMP) inhibitors, matrix metalloproteinase-12 (MMP-12) inhibitors, mucolytic agents, muscarinic M1 receptor antagonists, muscarinic M1 receptor antagonists / muscarinic M3 receptor antagonists, muscarinic (MARCKS) inhibitors, neurogenic agents, neuroactive agents, neurokinin NK1 receptor antagonists, neurokinin NK1 receptor &lt; RTI ID = 0.0 &gt; Antagonists, neurokinin NK2 receptor antagonists, neurokinin NK3 receptor antagonists, neurokinin NK2 receptor antagonists, neurokinin NK3 receptor antagonists, non-opioid analgesics, NSAIDs, nuclei (P38) kinase inhibitor, parasympathetic stimulant, parathyroid calcitonin, a peripheral chemoreceptor agonist, a phosphatidylinositol 3- (2-hydroxyphenyl) phosphatidylinositol 3-phosphate kinase inhibitor, (PDE-3) inhibitor, a phosphodiesterase inhibitor, a phosphodiesterase-4 inhibitor, a phosphodiesterase-7 inhibitor, a phosphodiesterase-4 inhibitor, 3 inhibitor / phosphodiesterase-4 (PDE-4) inhibitor, phosphodiesterase-3 (PDE-3) inhibitor / phosphodiesterase-5 (PDE- (PDE-4) inhibitor, phosphodiesterase-5 (PDE-5) inhibitor, phosphodiesterase-7 (PDE-7) inhibitor, prostaglandin D2 (PGD2) receptor antagonist , Prostaglandins, protease serine 8 (PRSS8) inhibitors, protein synthesis inhibitors, proteinase 3 (PRTN3) inhibitors, (SSAO) inhibitors, sex hormones (including steroids), Sirtuin 1 (SIRT1) activators, steroids, stimulants, and appetite suppressants, including, but not limited to, inhibitors, psychostimulants, radiopharmaceuticals, respiratory medications, sedatives, semicarbazide-sensitive amine oxidase (TXA2) receptor antagonists, thyroid agents, Toll-like receptor 9 (TLR9) agonists, neurotransmitters, transient &lt; RTI ID = 0.0 &gt; Receptor antagonist cation channel subfamily A / TRPA1 antagonist, tumor necrosis factor-α (TNFα) inhibitor, tumor necrosis factor superfamily member 4 (TNFSF4) inhibitor, vaccine (including influenza, measles, meningitis, Activators, vasodilators, and xanthines; Or a pharmaceutically acceptable salt, derivative, solvate, hydrate or polymorph thereof.

In another embodiment, the pharmaceutical active is selected from the group consisting of ciprofloxacin, cholestin, dihydroergotamine, fluticasone propionate, fluticasone propionate, formoterol, ipratropium, polyamicin B, rifampicin, Erythromycin, erythromycin, erythropoietin, erythromycin, erythromycin, erythromycin, erythromycin, erythromycin, erythromycin, erythromycin, erythromycin, (LMWH), insulin-like growth factor (IGF), insulinotropin, interferon alpha, interferon beta, interferon gamma, levofloxacin, romexclocassin, low molecular weight heparin ), Methicillin, tobramycin, vancomycin, vasopressin, beclometasone di propionate, budesonide, calcitonin, desmopressin, But are not limited to, ergotamine, fentanyl citrate, flurisolid, insulin (including substituted insulin and pro-insulin), mometasone furoate, salbutamol sulfate, salmeterol, ipratropium bromide, proinsulin, Insulin, insulin, synthetic insulin, X-ray contrast agent, alpha 1 antitrypsin, AZD1419, AZD1981, AZD3199, AZD5069, AZD5423, AZD8683, AZD9164, AZD9668, cyclosonide, cromolyn sodium, Wherein the tablet is selected from the group consisting of starch hydrolyzate, erythromycin, stin hydrochloride, erdostain, etamifylline hydrochloride, fenfϊride hydrochloride, plonysolid, glycopyrrolate, GSK1325756, GSK159802, GSK2190915, GSK2245840, GSK256066, GSK573719, GSK610677, GSK681323, GSK961081, , GW870086, hydrocortisone sodium succinate, indacaterol, revrikizumab, levocetirizine dihydrochloride, rosemapimode, MABA, Methylglutamate, oxytriamine hydrochloride, oxtriphylline, PF184, PF3526299, PF3635659, PF3526299, and PF3635659. The compositions of the present invention may be formulated as tablets, capsules, Pf3893787, PF4191834, PF4764793, PF610355, pyruvate acetate, pranlukast hydrate, procaterol hydrochloride, ceratologist, sodium pyruvate, TD4208, TD5959, theophylline, topilmilast, tulobuterol hydrochloride, Antimicrobial agents, antimetabolites, antimicrobial agents, antimicrobial agents, antimicrobial agents, antimicrobial agents, antimicrobial agents, antimicrobial agents, antimicrobial agents, Or a pharmaceutically acceptable salt, derivative, solvate, hydrate, or polymorph thereof.

In another embodiment, the pharmaceutical active is selected from the group consisting of 13-cis-retinoic acid, 5-fluorouracil, 9-nitrocamptothecin, AB1010, avathecept, acepiline piperazine, acetylcysteine, aclidinium bromide, ACT 129968, Alfentanil hydrochloride, alkaline phosphatase, almitrin mesylate, alpha 1, albuterol sulfosuccinate, albuterol sulfate, albuterol sulfate, alfentanil hydrochloride, alkaline phosphatase, Amlodipine, amitriptyline, amoxicillin, amitriptyline, amlodipine, amlodipine, amitriptyline, alpha 1 protease inhibitor, alpha-proline hydrochloride, Anti-CMV antibody, antiepileptic agent, papaveretum, antithrombin III, AP1500, ARRY006, atelolol, ATL1102, ATL844, AVE0675, AZD1419, AZD198 1, AZD3199, AZD5069, AZD5423, AZD8683, AZD9164, AZD9668, azelastine, azatrimidine, azithromycin, azlucillin, AZN6553, aztreonam, bacitracin, baclofen, bambuterol, Β-carotene, β-endorphin, β-interferon, bezafibrate, beztramide, BI671800, non-amoic acid amide, benzodiazepine, benzodiazepine, But are not limited to, disodium, vinobombo, BIO11006, bisperidene, bispecific antibodies, bisphosphonates, BMS639623, bromagepharm, bromocriptine, bocindolol, budesonide, budesonide acetonide, But are not limited to, hydrochloride, clathrate, butorphanolol tartrate, cardralazine, caffeine, calcitonin, camptothecin, cannquinum, canthus activity, But are not limited to, fenugreek, pin, carbenicillin, carbocysteine, carboplast, carpetanil citrate, camoterol, CAT354, sephacler, cephadoxil, cephalexin, cephalothin, sephalanol, Wherein the compound is selected from the group consisting of Pepin, Cepinoxin, Cefixime, Cefuroxime, Cefmetazole, Cellosynide, Cell Perazone, But are not limited to, ceftazidime, ceftavuten, ceftriaxone, ceftriaxone, cefuroxime, CEM315, cephalosyl, cephalexin, cephaloglycine, cephaloridine, cephalotin, cephapirin, Cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, Terbin hydrochloride, clinafloxacin, clonidine, Cortisone, corticolone, corticosterone, cortisol, cortisone, CP325366, CP4166, c-peptide, cromolyn sodium, CS003, CWF0710, Cyclophosphamide, cyclosporin A and other cyclosporin, cytarabine, dantrolene, attomycin, daurotropium, dabercin, deoxyribonuclease (Dnase), desmopressin, desocryptine, But are not limited to, dexamethasone, dexogestrel, dexamethasone, dextromomide, dextrofoxyphene, dezocine, diamorphine hydrochloride, diazepam, diclofenac, dicloxycin, dideoxyadenosine, dideoxyinosine, digoxin, digoxin, dihydrocodeine , Dihydroergotamine, dihydroergotamine tartrate, dihydroergoxin, diltiazem, DIMS0001, dipiphenone hydrochloride, dirislomycin, disodium palmitate Doronate, dopamine antagonist, toxin filine, doxorubicin, DRL2546, DW403, DX2300, econazole, EL246, ELAPYN, ELB353, ELKATONIN, enadolin, enalapril, angiogenic growth factor, endralazine, enkephalin, Erythromycin, erythropoietin (EPO), estradiol, estramustine, erythromycin, erythromycin, erythropoietin, erythropoietin, erythropoietin , Ethaminophylline hydrochloride, etoprotein citrate, ethyl morpholine hydrochloride, etofibrate, etoposide, etorphine hydrochloride, ETX9101, Factorix, factor IX insulin, factor viii, felbamate, , Fenofibrate, phenoterol, fenfidine hydrochloride, fentanyl citrate, pexopenadine, FHTCT4, flecainide, feloxacin, , Follicle stimulating hormone (FSH), formoterol, folliculamine, folliculamine, follicle stimulating hormone (FSH), formoterol, (GGF), gliclazide, glipizide, glucagon, glutathione, glutamate, glutamate, glutamate, glutamate, glutamate, (GLP-1), glucagon-like peptide thymosin alpha 1, glycopyrrolate, gramicidin, granulocyte colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GMCSF), GRC3886 Growth hormone releasing hormone (GHRH), GSK1325756, GSK159802, GSK2190915, GSK2245840, GSK256066, GSK573719, GSK610677, GSK681323, GSK961081, guineafenesin, GW870086, HAE1, sum Toggle (HGH), hydralazine, hydrochlorothiazide, hydrocodone, hydrocortisone, hydrocortisone (HGH), human growth hormone (HGH), heparin, hepatitis B vaccine, heparin, HF1020, HI164OV, HL028, HMT, HS- Indazole, indomethacin, indinavir, indomethacin, ibuprofen, ibuproxam, IC485, IL-4 inhibitors COSMIX, IMA026, IMD1041, imipenem, IMO2134, indacaterol, indinavir, indomethacin, Interferon alpha 1, interferon beta, interferon gamma, interleukin-1, interleukin-1 receptor, interleukin-1 receptor (including insulin, insulin, insulin, insulin-like growth factor (IGF) An antagonist, an interleukin-2, an interleukin-3, an interleukin-4, an interleukin-4R, an interleukin-6, an iodamic, an ipratropium, an ipratropium bromide, Ketamine, Ketoconazole, Ketoprofen, Ketotifene, Ketotifenfumarate, KM278, KPE06001, K-Strofatin, L971, Rbetalol, Lactobacillus Vaccine, LAS100977 Lecithin, lecithin, lecithin, lecithin, lecithin, lecithin, lecithin, lecithin, lecithin, lecithin, lecithin, Low molecular weight heparin (LMWH), luteinizing hormone-releasing hormone (LHRH), MABA (LHRH), lysophosphatidylcholine, , Mabuterol hydrochloride, macrophage colony stimulating factor (M-CSF), marshilukast, MDT011, messtaine hydrochloride, MEDI557, mefenamic acid, melphalan, MEM1414 , Methotinol hydrochloride, meropenem, mesylergen, metaproterenol sulfate, metergoline, methadone hydrochloride, methicillin, methotrexate, methotrimeprazine, methyldigosin, methylprednisolone, methipranolol , Methoprofen, metepoprine, meteprazole, metolazone, metoprolol, metoprolol tartrate, metronidazole, mexylin, meslocillin, myan serine, myconazole, myconezolinate, midazolam, mydecamycin, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Molecular Biology, Thrombin, napsilin, napiberrine, nalbuphine hydrochloride, naproxen, natural insulin, NCX1020, nedocromil, neomycin, nerve (NGF), nepalidil, nethilmicin, nicardipine, nicomorphine hydrochloride, nicorandil, nifedipine, niludipine, nimodipine, nitrazepam, nitrendipine, nitrocamptothecin, norfloxacin , NPB3, OC000459, octreotide, oproxacin, olanzapine, oleandomycin, allodasterol, omalizumab, opium, OPLCCL11LPM, OX2477, OX40, OX914, oxacillin, oxazepam, oxitropium bromide, (PTH), parogluryl hydrochloride, paju floc, paclitaxel hydrochloride, paclitaxel hydrochloride, paclitaxel hydrochloride, paclitaxel hydrochloride, paclitaxel hydrochloride, Peproxacin O, Penicillin G Venetamine, Penicillin G, Penicillin V, Pentamidine, Pentamidine Isethioate, Pentamorphone, Pentazocine, PEP03, Petidine (PDE) compound, picenadol hydrochloride, PF184, PF3526299, PF3635659, PF3893787, PF4191834, PF4764793, PF610355, phenazocine hydrobromide, phenopyridine hydrochloride, phenothiazine, Pyridoxal, pyrimidine, pyridoxal, pyridoxal, pyridoxal, pyridoxal, pyridoxal, pyridoxal, pyridoxal, pyridoxal, A prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, an agonist, POL6014, polymyxin B, pranlukast hydrate, prednisolone, prednisone, PT002, PT003, PT009, PT010, PUP1, PXS4159, PXS74, QAX028, QAX576, R7 &lt; RTI ID = 0.0 &gt; 103, Raloxifene, Rampolanin, RBx11082, REGN668, Remifentanil hydrochloride, Lefoterol, respiratory cell fusion virus antibody, RG7449, rifampicin, ripapentin, rocitamycin, roxithromycin, RPL554, RTA403, salbutamol sulfate , Salbutamol, salmeterol, salmeterolginate, SAR21609, SAR389644, SB656933, SCH527123, semi-synthetic insulin, ceratologist, simvastatin, cytarfloxacin, sobrerol, sodium pyruvate, sodium But are not limited to, cromoglycate, somatostatin, somatostatin, somatropin, sparfloxacin, spirulone mesylate, spiromycin, stilamine, STNM03, streptomycin, sufentanil citrate, sulfinaldiol hydrochloride, sulfinpyrazone, Tylidol, Sulprostone, Su Propenol, Swinolide A, Synthetic Insulin, TA106, Talinolol, TAPI, TARGALLERG I200, TARGALLERG I201, TARGALLERG I202, Taxol, Taxotere, (TPO), thiamine, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, Tochemicin, tolmicarst, tolmetin, toazocin mesylate, tosuocrosacin, TPI1100, TPI2200, tramadol hydrochloride, tranilast, trefetanil , Tromethasone hydrochloride, Tumor Necrosis Factor (TNF), UR5908, UR63325, urokinase, VAK694, TAM, Valium, vancomycin, vasopressin, verapamil, vidarabine, vidarabine phosphate sodium salt, Vitamin A, vitamin E succinate, VLA-4 inhibitor, X072NAB, X-ray contrast agent, xylomethazoline hydrochloride, zafiratin hydrochloride, zafirlukast, vinblastine, vincristine, vincristine, An analogue thereof, an agonist, an antagonist, an inhibitor from Lucast, and Gileetto; Or a pharmaceutically acceptable salt, derivative, solvate, hydrate, or polymorph thereof.

In reference to peptides and proteins, therapeutic peptides or proteins include synthetic, natural, glycosylated, non-glycosylated, pegylated forms, and their pharmaceutically active fragments and analogs.

Can be found in Martindale ' s The Extra Pharmacopoeia , 31st Edition (The Pharmaceutical Press, London, 1996) which is specifically incorporated by reference to the description of the type of pharmacologically active agent and the list of individual therapeutic agents within each type. Alternatively, a listing and list of suitable pharmaceutical active agents can be found in the Physicians Desk Reference (60th Ed., Pub. 2005). The disclosed pharmacologically active agents are commercially available and / or can be prepared by techniques known in the art. While the complete list of drugs for which the methods of the invention are suitable will be cumbersome to the present specification; Reference to the general pharmacopoeias listed above will enable those skilled in the art to select suitable pharmaceutical active agents that can be used in the preparation of complex particles comprising millable milling matrices and pharmaceutically active agents. It is also anticipated that the disclosed methods will include novel chemical entities (NCEs) and other therapeutic agents so that the new pharmaceutical active agents will be made in the future or will be commercially available.

Claims (79)

A method for manufacturing a composite particle for inhalation comprising a pharmaceutically active agent comprising the steps of:
a) providing composite particles comprising a pulverulent finely powdered matrix and a solid pharmaceutical active, wherein the pharmaceutically active agent has a median particle size of from 50 nm to 3 μm on a volume average basis; And
b) milling the composite particles in a mill without a milling body for a period of time sufficient to produce inhalable composite particles having a median aerodynamic diameter of between 1 μm and 20 μm. 2. The method of claim 1, wherein the inhalation composite particles comprise a solid pharmaceutical active having median particles of 50 nm to 3 占 퐉 on a volume average basis. The method of claim 1, wherein the inhalation composite particles have a median particle size of less than 10,000 nm in volume average size. The method of claim 1, wherein the inhalation complex particles are determined on a particle volume basis and have a D90 of less than or equal to 15,000 nm. The method of claim 1, wherein the particles for inhalation complexes are determined on a particle volume basis and have a D90 of greater than or equal to 2000 nm. The method of claim 1, wherein the particles for inhalation composite have a volume weighted average value (D4,3) of no more than 10,000 nm. The method of claim 1, wherein the particles for inhalation composite have a volume weighted average value (D4,3) of at least 1000 nm. The method of claim 1, wherein the inhalation composite particles are capable of providing an aerosol having a mass median aerodynamic diameter (MMAD) of at least 1 μm to 10 μm inhalable composite particles upon delivery from a dry powder inhaler. The method of claim 1, wherein the inhalation composite particles can provide an aerosol having a fine particle fraction (FPF) of at least about 10% of the emitted dose of the pharmaceutically active substance upon delivery from the dry powder inhaler. The method of claim 1, wherein the inhalation complex particles can provide an aerosol having a relative standard deviation (RSD) of the FPF of about 10% or less of the release dose of the pharmaceutically active agent. The composition of claim 1, wherein the inhalation composite particles are capable of providing an aerosol having a fine particle fraction (FPF) of at least about 30% of the total recovered dose of the pharmaceutically active substance upon delivery from the dry powder inhaler Way. 2. The method of claim 1, wherein the inhalation composite particles have a mass median aerodynamic diameter (MMAD) of at least about 10 [mu] m to about 10 [mu] m inhalation complex particles at delivery from the dry powder inhaler and a minimum of about 10% A method capable of providing an aerosol having an FPF. 13. The method according to claim 8 or 12, wherein the inhalation composite particles are capable of providing an aerosol having a mass median aerodynamic diameter (MMAD) of the inhalation composite particles of 1 [mu] m to 7 [mu] m upon delivery from a dry powder inhaler . The method according to claim 8 or 12, wherein the inhalation composite particles are capable of providing an aerosol having a mass median aerodynamic diameter (MMAD) of 1.5 microns to 5 microns inhalation composite particles upon delivery from a dry powder inhaler . 13. The method according to claim 8 or 12, wherein the inhalation composite particles are capable of providing an aerosol having a mass median aerodynamic diameter (MMAD) of inhalable complex particles of 2 [mu] m to 5 [mu] m upon delivery from a dry powder inhaler . 13. The method according to claim 8 or 12, wherein the inhalation composite particles are capable of providing an aerosol having a mass median aerodynamic diameter (MMAD) of inhaled complex particles of 2 [mu] m to 4 [mu] m upon delivery from a dry powder inhaler . The method of claim 1, wherein the inhalation composite particles can provide an aerosol having a fine particle fraction (FPF) of at least about 70% release capacity upon delivery from a dry powder inhaler. The method of claim 1, wherein the composite particles are capable of providing an aerosol having a relative standard deviation (RSD) of less than or equal to about 10% for at least three samples delivered from a dry powder inhaler. The method of claim 1, wherein the pharmaceutically active material in the provided composite particle has a median size of from about 50 nm to about 1000 nm. The method of claim 1, wherein the provided composite particles further comprise milling aids. 2. The method of claim 1 wherein the millable milling matrix is crystalline. 2. The method of claim 1, wherein the pharmaceutically active agent is crystalline. The method of claim 1, wherein the uniformity of the content of the solid pharmaceutical active agent dispersed in the composite particles has a percentage difference of less than or equal to about 5.0% from the average content. 3. The method of claim 1 wherein the content uniformity of the pharmaceutically active agent throughout the formulation has a percent relative standard deviation (RSD) of no more than about 5.0%. The method of claim 1, wherein the inhalation composite particles have a roughness ratio by surface area of at least about 1.1;
Wherein the specific surface area is measured using nitrogen absorption; And
Where the surface area is calculated from the spherical equivalent size determined by dry powder laser diffraction. The method of claim 1, wherein the composite particles have Rrms greater than or equal to about 15 nm selected and Rrms is measured using atomic force microscopy. 5. The method of claim 1, wherein the composite particles have Rrms greater than or equal to about 15 nm selected from the group consisting of Rrms, and the Rrms are measured using a white light interference measurement. The method of claim 1, wherein the composite particles have a median adhesion (F [50]) of less than or equal to about 150 nN as measured by atomic force microscopy. 2. The method of claim 1, wherein the weight of the composite particles deviates from an average weight distributed during dispensing from an automated or semiautomatic filing machine by no more than about 10 percent. 2. The method of claim 1 wherein the RSD from the average weight is less than or equal to about 10% when the number of samples measured is greater than 100 samples delivered from an automated or semi-automatic filing machine. The method of claim 1, wherein the step of providing the composite particles comprises the step of mixing the solid pharmaceutical active agent and the millable blend in a mill comprising a plurality of milling bodies for a time sufficient to produce composite particles comprising the milling matrix and the solid pharmaceutical active agent Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; finely divided matrix. 32. The method of claim 31, wherein dry milling comprises milling in a mill having a plurality of milling bodies. The method of claim 1, wherein the mill without a milling body is selected from the group consisting of a cutter mill, an end-runner mill, a roller mill, a hammer mill, a fluid energy mill, a pin mill, an impact mill, a mechanofusion mill, a beater mill, &Lt; / RTI &gt; The method of claim 1, wherein the millable milling matrix is selected from the group consisting of organic acids, organic bases, polyols, peptides, proteins, fats, fatty acids, amino acids, carbohydrates, phospholipids, triglycerides, detergents, , Hydrates, or polymorphs thereof. 35. The method of claim 34 wherein the carbohydrate is selected from the group consisting of mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, lactose, sucrose, raffinose, ribitol, maltose D-glucopyranosyl-D-mannitol (isomalt), or its pharmacologically acceptable salts, such as sorbose, sorbose, sorbose, sorbose, trehalose, maltodextrin, dextran, inulin, 1-O- Acceptable solvates, hydrates, or polymorphs thereof. 35. The method of claim 34, wherein the amino acid is selected from the group consisting of aspartate, glutamic acid, leucine, L-leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, Acetyl-L-cysteine, or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof. 35. The method of claim 34, wherein the millable milling matrix comprises lactose monohydrate and a diluent selected from the group consisting of sodium chloride, anhydrous lactose, mannitol, glucose, sucrose, trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl- Maltose, maltose, maltose, maltose, maltose, maltitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, Sodium citrate, sodium ascorbate. But are not limited to, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidyl glycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sodium lauryl sulfate, ; An optional one selected from PEG 6000, PEG 3000 Tween 80, Poloxamer 188, leucine, L-leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, &Lt; / RTI &gt; The method of claim 1, wherein the composite particles further comprise a second pharmaceutically active agent, the method comprising generating a composite particle of a matrix having a solid pharmaceutical active agent dispersed in a matrix and a second pharmaceutically active agent. 39. The method of claim 38, wherein the composite particles are delivered from a dry powder inhaler and analyzed by NGI with an induction port and a pre-separator to provide a ratio of fine particles of the first pharmaceutical active agent and second pharmaceutical active agent of less than about 1.2 How to get there. 39. The method of claim 38, wherein the analyte is delivered from the composite particle dry powder inhaler and analyzed by an NGI with an induction port and a pre-separator, having an MMAD uniformity ratio of about 1.2 or less, wherein each of the first and second pharmaceutical active agents Wherein the distribution is evaluated and used to calculate the MMAD for each composite particle. A composition for inhalation of pharmaceutically active composite particles prepared by the method of claim 1. A pharmaceutically active composition for inhalation comprising:
A plurality of composite particles comprising a millable milling matrix and a solid pharmaceutical active, wherein the composite particles of the milling matrix and the solid pharmaceutical active have a mass median aerodynamic diameter of from about 1 [mu] m to about 20 [mu] m; And the pharmaceutically active agent in the composite particle have an average particle size of about 50 nm to about 3 [mu] m. 43. The inhalable pharmaceutical composition of claim 42, wherein the inhaled complex particles comprise a solid pharmaceutical active having median particles of 50 nm to 3 占 퐉 on a volume average basis. 43. The inhalable pharmaceutical composition according to claim 42, wherein the inhalation complex particles have a median particle size of less than 10,000 nm in volume average size. 43. The pharmaceutical composition for inhalation according to claim 42, wherein the inhalation complex particles are determined on the basis of particle volume, and have a D90 of 15,000 nm or less. 43. The inhalable pharmaceutical composition of claim 42, wherein the inhaled complex particles are determined on a particle volume basis and have a D90 of at least 2000 nm. 43. The composite particle for inhalation according to claim 42, wherein the particles for inhalation composite have a volume-weighted average value (D4,3) of 10,000 nm or less. 43. The composite particle for inhalation according to claim 42, wherein the particle for inhalation composite has a volume-weighted average value (D4,3) of 1000 nm or more. 43. The inhalation composite particle of claim 42, wherein the inhalation composite particles can provide an aerosol having a mass median aerodynamic diameter (MMAD) of inhaled complex particles of 1 [mu] m to 10 [mu] m upon delivery from a dry powder inhaler. 43. The inhalable pharmaceutical composition of claim 42, wherein the inhalation complex particles can provide an aerosol having a fine particle fraction (FPF) of at least about 10% of the release dose of the pharmaceutically active substance upon delivery from the dry powder inhaler. 43. The inhalable pharmaceutical composition of claim 42, wherein the inhaled complex particles can provide an aerosol having a relative standard deviation (RSD) of the FPF of about 10% or less of the release dose of the pharmaceutically active agent. 43. The inhalable pharmaceutical composition of claim 42, wherein the inhaled complex particles are capable of providing an aerosol having a fine particle fraction (FPF) of at least about 30% of the total recovered dose of the pharmaceutically active substance upon delivery from the dry powder inhaler . 50. The method of claim 49, wherein the inhalation composite particles have a mass median aerodynamic diameter (MMAD) of at least about 1 [mu] m to about 10 [mu] m inhalation complex particles at delivery from a dry powder inhaler and a minimum of about 10% An inhalable pharmaceutical composition capable of providing an aerosol having an FPF. 50. The inhalable pharmaceutical composition of claim 49, wherein the inhalation composite particles are capable of providing an aerosol having a mass median aerodynamic diameter (MMAD) of inhaled complex particles of from 1 [mu] m to 7 [mu] m upon delivery from a dry powder inhaler . 50. The inhalable pharmaceutical composition of claim 49, wherein the inhalation composite particles are capable of providing an aerosol having a median aerodynamic diameter (MMAD) of from 1.5 [mu] m to 5 [mu] m inhalation complex particles upon delivery from a dry powder inhaler . 50. The inhalable pharmaceutical composition according to claim 49, wherein the inhalation composite particles are capable of providing an aerosol having a mass median aerodynamic diameter (MMAD) of inhaled complex particles of 2 [mu] m to 5 [mu] m upon delivery from a dry powder inhaler . 50. The inhalable pharmaceutical composition according to claim 49, wherein the inhalation composite particles are capable of providing an aerosol having a median aerodynamic diameter (MMAD) of from 2 [mu] m to 4 [mu] m inhalation composite particles upon delivery from a dry powder inhaler . 43. The inhalable pharmaceutical composition of claim 42, wherein the inhalable complex particles can provide an aerosol having a fine particle fraction (FPF) of at least about 70% release capacity upon delivery from a dry powder inhaler. 43. The inhalable pharmaceutical composition of claim 42, wherein the composite particles can provide an aerosol having a relative standard deviation (RSD) of less than or equal to about 10% for at least three samples delivered from a dry powder inhaler. 43. The pharmaceutical composition for inhalation according to claim 42, wherein the pharmaceutically active substance in the provided composite particle has a median size of from about 50 nm to about 1000 nm. 43. The inhalable pharmaceutical composition of claim 42, wherein the provided composite particles further comprise a milling aid. 43. The inhalable pharmaceutical composition of claim 42, wherein the millable milling matrix is crystalline. 43. The inhalable pharmaceutical composition of claim 42, wherein the pharmaceutically active agent is crystalline. 43. The pharmaceutical composition for inhalation according to claim 42, wherein the uniformity of the content of the solid pharmaceutical active agent dispersed in the composite particles has a percentage difference of not more than about 5.0% from the average content. 43. The pharmaceutical composition for inhalation according to claim 42, wherein the content uniformity of the pharmaceutically active agent throughout the formulation has a percent relative standard deviation (RSD) of about 5.0% or less. 43. The inhalable pharmaceutical composition of claim 42, wherein the inhalation complex particles have a roughness ratio by surface area of at least about 1.1;
Wherein the specific surface area is measured using nitrogen absorption; And
Where the surface area is calculated from the spherical equivalent size determined by dry powder laser diffraction. 43. The inhalable pharmaceutical composition of claim 42, wherein the composite particles have Rrms greater than or equal to a height selected from about 15 nm and Rrms is measured using atomic force microscopy. 43. The pharmaceutical composition according to claim 42, wherein the composite particles have Rrms greater than or equal to a height selected from about 15 nm and Rrms is measured using white light interference measurement. 43. The pharmaceutical composition according to claim 42, wherein the composite particles have a median adhesion (F [50]) of about 150 nN or less as measured by atomic force microscopy. 43. The pharmaceutical composition according to claim 42, wherein the weight of the composite particles deviates from the average weight distributed at the time of dispensing from an automated or semi-automated pilling machine by no more than about 10 percent. 43. The pharmaceutical composition according to claim 42, wherein the RSD from the average weight is less than or equal to about 10% when the number of samples measured is greater than or equal to 100 samples delivered from an automatic or semi-automatic filing machine. 43. The inhalable pharmaceutical composition of claim 42, wherein the composite particles further comprise a second pharmaceutically active agent, the method comprising administering to the patient a composition for inhalation which produces complex particles of a matrix having a solid pharmaceutical active agent dispersed in a matrix and a second pharmaceutical active agent . 43. The method of claim 42, wherein the composite particles are delivered from a dry powder inhaler and analyzed by NGI with an induction port and a pre-separator to provide a ratio of fine particles of the first pharmaceutical active agent and second pharmaceutical active agent of less than about 1.2 Lt; / RTI &gt; 43. The method of claim 42, wherein the composite particles are delivered from a dry powder inhaler and have an MMAD uniformity ratio of less than or equal to about 1.2 when analyzed by NGI with an induction port and a pre-separator, wherein each of the first and second pharmaceutical active agents Is evaluated and used to calculate the MMAD for each composite particle, respectively. 74. The pharmaceutical composition according to any one of claims 41 to 74, wherein the composition is formulated in unit dosage form. 78. The pharmaceutical composition of claim 75, comprising a gelatin capsule. 78. The pharmaceutical composition of claim 75, wherein the composition is suitable for use with a dry powder inhaler. A dry powder inhaler comprising the pharmaceutical composition of any one of claims 41 to 74. A dry powder inhaler comprising the pharmaceutical composition of claim 76.

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